Novel compounds

ABSTRACT

The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase L1 (UCHL1). The invention further relates to the use of DUB inhibitors in the treatment of cancer and other indications. Compounds of the invention include compounds having the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R8 are as defined herein.

The present invention relates to novel compounds and methods for themanufacture of inhibitors of deubiquitylating enzymes (DUBs). Inparticular, the invention relates to the inhibition of ubiquitinC-terminal hydrolase L1 (UCHL1). The invention further relates to theuse of DUB inhibitors in the treatment of cancer and methods ofscreening.

BACKGROUND TO THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Ubiquitin is a small protein consisting of 76 amino acids that isimportant for the regulation of protein function in the cell.Ubiquitylation and deubiquitylation are enzymatically mediated processesby which ubiquitin is covalently bound or cleaved from a target protein.These processes have been implicated in the regulation of many cellularfunctions including cell cycle progression, apoptosis, modification ofcell surface receptors, regulation of DNA transcription and DNA repair.Thus, the ubiquitin system has been implicated in the pathogenesis ofnumerous disease states including inflammation, viral infection,metabolic dysfunction, CNS disorders, and oncogenesis (Clague et al.,Physiol Rev 93:1289-1315, 2013). A number of ubiquitin-like (Ubls)molecules have been identified that regulate protein functions in cellsin a similar manner to ubiquitin.

Ubiquitin and Ubls molecules are cleaved from proteins by enzymes calledisopeptidases or deubiquitinating enzymes (DUBs), of which there areapproximately 95 DUBs in human cells, divided into sub-families based onsequence homology: ubiquitin C-terminal hydrolases (UCHs),ubiquitin-specific proteases (USPs), ovarian tumour proteases (OTUs),Machado-Josephin domain proteases (MJDs), JAB1/MPN/MOV34metalloproteases (JAMMs) or Sentrin-specific proteases (SENPs). DUBs canprocess ubiquitin or ubiquitin-like adducts. A number of DUBs have beenlinked to various diseases including cancer, inflammation,neurodegenerative diseases and anti-infectives (Kim K H et al., CurrPharm Des. 2013; 19(22):4039-52; Nicholson B et al., J Biomol Screen.2014 Mar. 14:19(7); 989-999; Ristic G et al., Front Mol Neurosci. 2014Aug. 19; 7:72; Ashida H et al., Nat Rev Microbiol. 2014 June;12(6):399-413. The ubiquitin C-terminal hydrolase (UCH) family,consisting of UCHL1, UCHL3, UCHL5, and BAP1, are cysteine proteases thatoperate through an active site thiol. UCHs are thought to be involved inthe processing and recycling of ubiquitin and to preferentially cleavesmall protein substrates. UCHL1 is a 223 amino acid protein whoseexpression is normally limited to the brain, peripheral nervous system,ovaries and testis in mammals. However, UCHL1 has been reported to beup-regulated in several pathological conditions, including tumourtissues, COPD, stroke, Parkinson's disease, Alzheimer's disease,neuropathic pain or lysosomal storage disorders. Furthermore, UCHL1functions as an oncogene in the progression of many cancers includingbreast, lymphoma, colorectal cancer, osteosarcoma, pancreatic and nonsmall cell lung carcinoma and is inversely correlated with patientsurvival (Hurst-Kennedy et al., Biochem Res Int, 2012; Hussain et al.,Leukemia 24:1641-1655, 2010). Pharmacological inhibition of UCHL1 wouldthus serve as novel treatment for pathologies such as cancers.

The ubiquitin-proteasome system has gained interest as a target for thetreatment of cancer following the approval of the proteasome inhibitorbortezomib (Velcade®) for the treatment of multiple myeloma. Extendedtreatment with bortezomib is limited by its associated toxicity and drugresistance. However, therapeutic strategies that target specific aspectsof the ubiquitin-proteasome pathway upstream of the proteaseome, such asDUBs, are predicted to be better tolerated (Bedford et al., Nature Rev10:29-46, 2011). To date, although there have been a handful ofinhibitors published in the literature (for a review see: Lill andWertz, Trends in Pharmaceutical Sciences, 35 (4), 2014), there have beenno reports of DUB inhibitors that have successfully entered the clinic.Thus, there is a need for compounds and pharmaceutical compositions toinhibit DUBs such as UCHL1, USP6 or USP30 for the treatment of cancer orother indications where DUB activity is observed. Alternative DUBs thathave also been suggested to be potential therapeutic targets for thetreatment of cancer include USP1, USP2, USP4, USP6, USP7, USP8, USP9x,USP10, USP11, USP13, USP14, USP17, USP28. Additional indications whereDUB inhibition may prove beneficial include CNS disorders (e.g. USP30,USP14) or inflammation (e.g. A20, CYLD).

SUMMARY OF THE INVENTION

In accordance with a first aspect of the invention there is provided acompound of formula (I)

A compound having the formula (I)

or a pharmaceutically acceptable salt thereof, wherein:R₁ represents a 5 to 10 membered heteroaryl ring which may be optionallysubstituted; andR₂, R₃, R₄, R₅, R₆ and R₈ each independently represent a hydrogen atom,cyano, an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₁-C₆ alkoxy group, one or more spirocyclic groups where R₃ is linked toR₄, R₅ is linked to R₆ or R₈ is linked to R₇, or R₂ is linked to R₈ toform an optionally substituted C₃-C₄ cycloalkyl ring, or R₆ is linked toR₇ to form an optionally substituted C₃-C₄ cycloalkyl ring; andR₇ represents a hydrogen atom, a fluorine atom, cyano, an optionallysubstituted C₁-C₃ alkyl, an optionally substituted C₁-C₃ alkoxy group oran optionally substituted aryl or 5 to 6 membered heteroaryl ring, or islinked to R₈ to form a spirocyclic group, or is linked to R₆ to form anoptionally substituted C₃-C₄ cycloalkyl ring.

R₁ may represent a 5 to 10 membered heteroaryl ring substituted with oneor more of Q₁-(R₉)_(n), wherein:

n is 0 or 1Q₁ represents a hydrogen atom, a halogen atom, cyano, a covalent bond,—NR₁₀—, —CONR₁₀—, —NR₁₀CO—, an oxygen atom, oxo, nitro, —S(O)_(m)—,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, —CO—, —SO₂R₁₁,—NR₁₁R₁₂, —NR₁₁COR₁₂, —NR₁₀CONR₁₁R₁₂, —CONR₁₁R₁₂, —CO₂R₁₁, —NR₁₁CO₂R₁₂,—SO₂NR₁₁R₁₂, —CONR₁₁, —C(O)R₁₁, —NR₁₁SO₂R₁₂ NR₁₁SO₂NR₁₃R₁₄ and SO₂NR₁₁or an optionally substituted C₁-C₆ alkylene, —C₂-C₆ alkenylene or —C₁-C₆alkyl group;m is 0, 1 or 2;R₁₀, R₁₁ and R₁₂ each independently represent a hydrogen atom or anoptionally substituted C₁-C₆ alkyl, or an optionally substituted C₁-C₆alkylene group.

When n is 1, R₉ represents an optionally substituted 3 to 10 memberedheterocyclyl, heteroaryl, aryl or cycloalkyl ring. (When n is 0, Q ispresent and R₉ is absent).

R₉ may be optionally substituted with one or more substituents selectedfrom halogen, optionally substituted C₁-C₆ haloalkyl, optionallysubstituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, oxo, cyano, nitro, optionallysubstituted heterocyclyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted aryl, -Q₂-NR₁₃CONR₁₄R₁₅,-Q₂-NR₁₃R₁₄, -Q₂-NR₁₃COR₁₄, -Q₂-COR₁₃, -Q₂-SO₂R₁₃, -Q₂-CONR₁₃,Q₂-CONR₁₃R₁₄, -Q₂-CO₂R₁₃, -Q₂-SO₂NR₁₃R₁₄, -Q₂-NR₁₃SO₂R₁₄ and-Q₂-NR₁₃SO₂NR₁₄R₁₅; wherein

Q₂ represents a covalent bond or a C₁-C₆ alkylene or C₂-C₆ alkenylenegroup; andR₁₃, R₁₄ and R₁₅ each independently represent hydrogen or an optionallysubstituted C₁-C₆ alkyl, or an optionally substituted heterocyclyl, oran optionally substituted heteroaryl, or an optionally substituted aryl,or an optionally substituted cycloalkyl.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides an image of FLAG-UCHL1 purified from mammalian cells.FLAG-purified protein or the indicated concentrations of BSA wereseparated by SDS-PAGE and stained with Imperial (Pierce Biotechnology).

FIG. 2 is a graph showing proteolytic activity of purified FLAG-UCHL1using a fluorescence polarisation assay. Various volumes of purifiedUCHL1 as indicated were incubated with a TAMRA labelled peptide linkedto ubiquitin via an isopeptide bond.

DETAILED DESCRIPTION OF THE INVENTION

Where any group of the compounds of Formula (I) have been referred to asoptionally substituted, this group may be substituted or unsubstituted.Substitution may be by one or more of the specified substituents whichmay be the same or different. It will be appreciated that the number andnature of substituents will be selected to avoid any stericallyundesirable combinations.

In the context of the present specification, unless otherwise stated analkyl, alkenyl, or alkynyl substituent group or an alkyl, alkenyl moietyin a substituent group may be linear or branched. Alkyl and alkenylchains may also include intervening heteroatoms such as oxygen.

C_(x)-C_(y) alkyl refers to a saturated aliphatic hydrocarbon grouphaving x-y carbon atoms which may be linear or branched. For exampleC₁-C₆ alkyl contains from 1 to 6 carbon atoms. “Branched” means that atleast one carbon branch point is present in the group. For example,tert-butyl and isopropyl are both branched groups. Examples of C₁-C₆alkyl groups include methyl, ethyl, propyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,neopentyl and n-hexyl.

A C_(x)-C_(y) alkylene group or moiety may be linear or branched andrefers to a divalent hydrocarbon group having one less hydrogen atomfrom C_(x)-C_(y) alkyl as defined above. Examples of C₁-C₆ alkylenegroups include methylene, ethylene, n-propylene, n-butylene,methylmethylene and dimethylmethylene.

C₂-C₆ alkenyl refers to a linear or branched hydrocarbon chain radicalcontaining at least two carbon atoms and at least one double bond.Examples of alkenyl groups include ethenyl, propenyl, 2-propenyl,1-butenyl, 2-butenyl, 1-hexenyl, 2-methyl-1-propenyl, 1,2-butadienyl,1,3-pentadienyl, 1,4-pentadienyl and 1-hexadienyl.

C₂-C₆ alkynyl refers to a linear or branched hydrocarbon chain radicalcontaining at least two carbon atoms and at least one triple bond.Examples of alkynyl groups include ethynyl, propynyl, 2-propynyl,1-butynyl, 2-butynyl and 1-hexynyl.

C₁-C₆ alkoxy refers to a group or part of a group having an—O—C_(x)-C_(y) alkyl group according to the definition of C_(x)-C_(y)alkyl above. Examples of C₁-C₆alkoxy include methoxy, ethoxy, propoxy,isopropoxy, butoxy, pentoxy and hexoxy.

C₁-C₆ haloalkyl and C₁-C₆ haloalkoxy refers to a C_(x)-C_(y) alkyl groupas defined above wherein at least one hydrogen atom is replaced with ahalogen atom. Examples of C₁-C₆haloalkyl groups include fluoromethyl,difluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl,fluoromethoxy, difluoromethoxy and trifluoromethoxy.

C₁-C₆ hydroxyalkyl refers to C_(x)-C_(y) alkyl group as defined abovewherein at least one hydrogen atom is replaced with a hydroxy (—OH)group. Examples of hydroxy C₁₋₆ alkyl groups include hydroxymethyl,hydroxyethyl, dihydroxyethyl, hydroxypropyl and hydroxyisopropyl.

The term “halogen” or “halo” refers to chlorine, bromine, fluorine oriodine atoms.

For the avoidance of doubt it will be understood that a 3 to 10 memberedheteroaryl, aryl, cycloalkyl or heterocyclic ring as defined accordingto R₁ or R₉ does not include any unstable ring structures or any O—O,O—S or S—S bonds and that a substituent if present may be attached toany suitable ring atom which may be a carbon atom or a heteroatom.Substitution on a ring may also include a change in the ring atom at theposition of the substitution. For example, substitution on a phenyl ringmay include a change in the ring atom at the position of substitutionfrom carbon to nitrogen, resulting in a pyridine ring. The 3 to 10membered heteroaryl, aryl, cycloalkyl or heterocyclic ring may bemonocyclic or bicyclic.

“C_(x)-C_(y) cycloalkyl” refers to a cyclic non-aromatic hydrocarbongroup of x-y carbon atoms. For example C₃-C₈ cycloalkyl refers to ahydrocarbon ring containing 3-8 carbon atoms. Examples of C₃-C₈cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopentyl, cyclohexyl cycloheptyl and cyclooctyl.

An “aryl” group/moiety refers to any monocyclic or bicyclic hydrocarbongroup comprising at least one aromatic group, for example having up to12 carbon atom ring members. Examples of aryl groups include phenyl,naphthyl, tetrahydronaphthyl and biphenyl.

“Heteroaryl” groups may be monocyclic or bicyclic. Bicyclic rings may befused aromatic rings where both rings are aromatic or may be fused ringswhere one of the rings is non aromatic. In the case of R1, the ringattached to the amide nitrogen is an aromatic ring, which can be fusedto a further aromatic or non-aromatic ring. Heteroaryl rings comprise 1,2 or 3 heteroatoms selected from oxygen, sulphur and nitrogen. When theheteroatom is nitrogen it may be oxidised. Examples of heteroaryl groupsinclude pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl,thiophenyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl,furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazinanyl, tetrazolyl, thiadiazolyl, benzofuranyl, isobenzofuranyl,benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl,napthyridinyl, pteridinyl, pyrazinyl, 4H-quinolizinyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl,pyrazolopyridinyl, thiazolopyridinyl, indolinyl, isoindolinyl,triazinyl, pyridazinyl, and quinoxalinyl.

“Heterocyclyl” groups may also be moncyclic or comprise 2 or more fusedrings which may be saturated or partially unsaturated comprising 1, 2 or3 heteroatoms selected from oxygen, sulphur and nitrogen. Examples ofheterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl,azepanyl, diazepanyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl,2,5-dihydrofuranyl), 4,5-dihydro-1H-maleimido, dioxolanyl, morpholinyl,oxazolidinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl,dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), dioxanyl,hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, pyridazinyl,4H-quinolizinyl, quinuclinyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetramethylenesulfoxide,thiazolidinyl, hydantoinyl, benzopyranyl, tetrahydrothiazolopyridinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl,tetrahydropyrazolopyrazinyl and tetrahydrothiazoloazepinyl.

“Optionally substituted” as applied to any group means that the saidgroup may if desired be substituted with one or more substituents, whichmay be the same or different. The optional substituents within thedefinitions of R₂, R₃, R₄, R₅, R₆ and R₈ may include halo, deutero, C₁₋₃alkyl, C₁₋₃ alkoxy, cyano, amino, nitro or SF₅ (a known mimetic of NO₂).Examples of suitable substituents for all remaining “substituted” and“optionally substituted” moieties, including rings R₁ and R₉ may includehalo, deutero, C₁₋₃ alkyl, hydroxy, C₁₋₃ alkoxy, cyano, amino, nitro,oxo, aryl, heteroaryl, heterocyclyl, C₃-C₆ cycloalkyl, C₁₋₃ alkylamino,C₂₋₆ alkenylamino, di-C₁₋₃ alkylamino, C₁₋₃ acylamino, di-C₁₋₃acylamino, carboxy, C₁₋₃ alkoxycarbonyl, carbamoyl, mono-C₁₋₃ carbamoyl,di-C₁₋₃ carbamoyl or any of the above in which a hydrocarbyl moiety isitself substituted by halo. In groups containing an oxygen atom such ashydroxy and alkoxy, the oxygen atom can be replaced with sulphur to makegroups such as thio (SH) and thio-alkyl (S-alkyl). Optional substituentstherefore include groups such as S-methyl. In thio-alkyl groups, thesulphur atom may be further oxidised to make a sulfoxide or sulfone, andthus optional substituents therefore includes groups such as S(O)-alkyland S(O)₂-alkyl.

Substituted groups thus include for example CN, CFH₂, CF₂H, CF₃, OCF₃,CH₂NH₂, CH₂OH, CH₂CN, CH₂SCH₃, CH₂OCH₃, OMe, OEt, OPr, Me, Et, t-Bu,—OCH₂O—, CO₂Me, C(O)Me, i-Pr, SCF₃, SO₂Me, NMe₂ etc. In the case of arylgroups, the substitutions may be in the form of rings from adjacentcarbon atoms in the aryl ring, for example cyclic acetals such asO—CH₂—O.

The term “treat” or “treating” or “treatment” includes prophylaxis andmeans to ameliorate, alleviate symptoms, eliminate the causation of thesymptoms either on a temporary or permanent basis, or to prevent or slowthe appearance of symptoms of the named disorder or condition. Thecompounds of the invention are useful in the treatment of humans andnon-human animals.

The dose of the compound is that amount effective to prevent occurrenceof the symptoms of the disorder or to treat some symptoms of thedisorder from which the patient suffers. By “effective amount” or“therapeutically effective amount” or “effective dose” is meant thatamount sufficient to elicit the desired pharmacological or therapeuticeffects, thus resulting in effective prevention or treatment of thedisorder. Prevention of the disorder is manifested by delaying the onsetof the symptoms of the disorder to a medically significant extent.Treatment of the disorder is manifested by a decrease in the symptomsassociated with the disorder or an amelioration of the reoccurrence ofthe symptoms of the disorder.

Pharmaceutically acceptable salts of the compounds of the inventioninclude but are not limited to addition salts (for example phosphates,nitrates, sulphates, borates, acetates, maleates, citrates, fumarates,succinates, methanesulphonates, benzoates, salicylates andhydrohalides), salts derived from inorganic bases (such as lithium,potassium and sodium), salts of amino acids (such as glycine, alanine,valine, leucine, isoleucine, cysteine, methionine and proline),inorganic bases (such as triethylamine, hydroxide, choline, thiamine andN—N′-diacetylethylenediamine). Other pharmaceutically acceptable saltsinclude ammonium salts, substituted ammonium salts and aluminium salts.Further pharmaceutically acceptable salts include quaternary ammoniumsalts of the compounds of formula (I).

General methods for the production of salts are well known to the personskilled in the art. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compoundwith one or more equivalents of an appropriate acid or base, optionallyin a solvent, or in a medium in which the salt is insoluble, followed byremoval of said solvent, or said medium, using standard techniques (e.g.in vacuo, by freeze-drying or by filtration). Salts may also be preparedby exchanging a counter-ion of a compound in the form of a salt withanother counter-ion, for example using a suitable ion exchange resin.

Where compounds of the invention exist in different enantiomeric and/ordiastereoisomeric forms, the invention relates to these compoundsprepared as isomeric mixtures or racemates whether present in anoptically pure form or as mixtures with other isomers. Enantiomersdiffer only in their ability to rotate plane-polarized light by equalamounts in opposite directions and are denoted as the (+)/(S) or (−)/(R)forms respectively. Individual enantiomers or isomers may be prepared bymethods known in the art, such as optical resolution of products orintermediates (for example chiral chromatographic separation e.g. chiralHPLC, or an enantiomeric synthesis approach). Similarly where compoundsof the invention exist as alternative tautomeric forms e.g. keto/enol,amide/imidic acid, the invention relates to the individual tautomers inisolation, and to mixtures of the tautomers in all proportions.

Included herein is the compound according to formula (II)

or a pharmaceutically acceptable salt thereof, wherein:R₁ represents a 5 to 10 membered heteroaryl ring which may be optionallysubstituted; andR₂, R₃, R₄, R₅, R₆ and R₈ each independently represent a hydrogen atom,cyano, an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₁-C₆ alkoxy group, one or more spirocyclic groups where R₃ is linked toR₄, R₅ is linked to R₆ or R₈ is linked to R₇, or R₂ is linked to R₈ toform an optionally substituted C₃-C₄ cycloalkyl ring, or R₆ is linked toR₇ to form an optionally substituted C₃-C₄ cycloalkyl ring; andR₇ represents a hydrogen atom, a fluorine atom, cyano, an optionallysubstituted C₁-C₃ alkyl, an optionally substituted C₁-C₃ alkoxy group oran optionally substituted aryl or heteroaryl ring or is linked to R₈ toform a spirocyclic group, or is linked to R₆ to form an optionallysubstituted C₃-C₄ cycloalkyl ring.

In one embodiment, R₁ represents a 5 to 10 membered heteroaryl ringwhich may be optionally substituted; and

R₂, R₃, R₄, R₅, R₆ and R₈ each independently represent a hydrogen atom,cyano, an optionally substituted C₁-C₃ alkyl, an optionally substitutedC₁-C₃ alkoxy group, one or more spirocyclic groups where R₃ is linked toR₄, R₅ is linked to R₆ or R₈ is linked to R₇, or R₂ is linked to R₈ toform a C₃-C₄ cycloalkyl ring; andR₇ represents a hydrogen atom, cyano, an optionally substituted C₁-C₃alkyl, an optionally substituted C₁-C₃ alkoxy group or an optionallysubstituted aryl or heteroaryl ring or is linked to R₈ to form aspirocyclic group.

Where R₃ and R₄ are different, the R₃ group can be cis or trans inrelation to the amide. Compounds are preferably cis when R₄ is H. WhenR₃=Me and R₂═R₄═H the compound may be represented according to formula(III)

Isotopes

The compounds described herein may contain one or more isotopicsubstitutions, and a reference to a particular element includes withinits scope all isotopes of the element. For example, a reference tohydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly,references to carbon and oxygen include within their scope respectively¹²C, ¹³C and ¹⁴C and 160 and 180. Examples of isotopes include ²H, ³H,¹¹H, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P and³⁵S.

In an analogous manner, a reference to a particular functional groupalso includes within its scope isotopic variations, unless the contextindicates otherwise. For example, a reference to an alkyl group such asan ethyl group also covers variations in which one or more of thehydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment,the compounds contain no radioactive isotopes. Such compounds arepreferred for therapeutic use. In another embodiment, however, thecompounds may contain one or more radioisotopes. Compounds containingsuch radioisotopes may be useful in a diagnostic context.

Certain isotopically labelled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes i.e. ³Hand ¹⁴C are particularly useful for this purpose in view of their easeof incorporation and ready means of detection. Substitution with heavierisotopes i.e. ²H, may afford certain therapeutic advantages resultingfrom greater metabolic stability, for example, increased in vivohalf-life or reduced dosage requirements, and hence may be preferred insome circumstances. Substitution with positron emitting isotopes, suchas ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography(PET) studies for examining receptor occupancy. Isotopically labelledcompounds of formula (I) can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying examples and preparations usingan appropriate isotopically labelled reagent in place of the nonlabelled reagent previously employed.

Crystalline and Amorphous Forms

The compounds of formula (I) may exist in crystalline or amorphous formand some of the crystalline forms may exist as polymorphs, which areincluded within the scope of the present invention. Polymorphic forms ofcompounds of formula (I) may be characterised and differentiated using anumber of conventional analytical techniques, including, but not limitedto, infra red spectra, Raman spectra, X-ray powder diffraction,differential scanning calorimetry, thermogravimetric analysis and solidstate nuclear magnetic resonance.

Accordingly, in further embodiments, the invention provides a compoundaccording to any described embodiments in a crystalline form. Thecompound may be from 50% to 100% crystalline, and more particularly isat least 50% crystalline, or at least 60% crystalline, or at least 70%crystalline, or at least 80% crystalline, or at least 90% crystalline,or at least 95% crystalline, or at least 98% crystalline, or at least99% crystalline, or at least 99.5% crystalline, or at least 99.9%crystalline, for example 100% crystalline. The compound mayalternatively be in an amorphous form.

The invention described herein relates to all crystal forms, solvatesand hydrates of any of the disclosed compounds however so prepared. Tothe extent that any of the compounds disclosed herein have acid or basiccentres such as carboxylates or amino groups, then all salt forms ofsaid compounds are included herein. In the case of pharmaceutical uses,the salt should be seen as being a pharmaceutically acceptable salt.

The invention relates to any solvates of the compounds and their salts.Preferred solvates are solvates formed by the incorporation into thesolid state structure (e.g. crystal structure) of the compounds of theinvention of molecules of a non-toxic pharmaceutically acceptablesolvent (referred to below as the solvating solvent). Examples of suchsolvents include water, alcohols (such as ethanol, isopropanol andbutanol) and dimethylsulfoxide. Solvates can be prepared byrecrystallising the compounds of the invention with a solvent or mixtureof solvents containing the solvating solvent. Whether or not a solvatehas been formed in any given instance can be determined by subjectingcrystals of the compound to analysis using well known and standardtechniques such as thermogravimetric analysis (TGE), differentialscanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.Particular solvates may be hydrates, and examples of hydrates includehemihydrates, monohydrates and dihydrates. For a more detaileddiscussion of solvates and the methods used to make and characterisethem, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition,published by SSCI, Inc of West Lafayette, Ind., USA, 1999, ISBN0-967-06710-3.

The invention relates to pharmaceutically functional derivatives ofcompounds as defined herein including ester derivatives and/orderivatives that have, or provide for, the same biological functionand/or activity as any relevant compound of the invention. Thus, for thepurposes of this invention, the term also includes prodrugs of compoundsas defined herein.

The term “prodrug” of a relevant compound includes any compound that,following oral or parenteral administration, is metabolised in vivo toform that compound in an experimentally-detectable amount, and within apredetermined time (e.g. within a dosing interval of between 6 and 24hours (i.e. once to four times daily).

Prodrugs of compounds may be prepared by modifying functional groupspresent on the compound in such a way that the modifications arecleaved, in vivo when such prodrug is administered to a mammaliansubject. The modifications typically are achieved by synthesizing theparent compound with a prodrug substituent. Prodrugs include compoundswherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in acompound is bonded to any group that may be cleaved in vivo toregenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonylgroup, respectively.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxyl functional groups, ester groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. 1-92, Elsevier, New York-Oxford (1985).

Compounds of the invention may be metabolised in vivo. Metabolites ofcompounds of formula (I) are also within the scope of the presentinvention. The term ‘metabolites’ refers to all molecules derived fromany of the compounds according to the present invention in a cell ororganism, preferably mammal. Preferably the term the term relates tomolecules which differ from any molecule which is present in any suchcell or organism under physiological conditions.

A treatment defined herein may be applied as a sole therapy of mayinvolve, in addition to the compounds of the invention, conventionalsurgery or radiotherapy or chemotherapy. Furthermore, compounds offormula (I) can also be used in combination with existing therapeuticagents for the treatment of cancer, including small moleculetherapeutics or antibody based therapeutics.

The disclosure includes compound having the formula (I)

or a pharmaceutically acceptable salt thereof, wherein:R₁ represents a 5 to 10 membered heteroaryl ring which may be optionallysubstituted;R₂, R₃, R₄, R₅, R₆ and R₈ each independently represent a hydrogen atom,cyano, an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₁-C₆ alkoxy group, one or more spirocyclic groups where R₃ is linked toR₄, R₅ is linked to R₆ or R₈ is linked to R₇, or R₂ is linked to R₈ toform an optionally substituted C₃-C₄ cycloalkyl ring, R₆ is linked to R₇to form an optionally substituted C₃-C₄ cycloalkyl ring; andR₇ represents a hydrogen atom, a fluorine atom, cyano, an optionallysubstituted C₁-C₃ alkyl, an optionally substituted C₁-C₃ alkoxy group oran optionally substituted aryl or heteroaryl ring, or is linked to R₆ toform a spirocyclic group, or is linked to R₆ to form an optionallysubstituted C₃-C₄ cycloalkyl ring.

In one embodiment, R₁ represents a 5 to 10 membered heteroaryl ringwhich may be optionally substituted;

R₂, R₃, R₄, R₅, R₆ and R₈ each independently represent a hydrogen atom,cyano, an optionally substituted C₁-C₃ alkyl, an optionally substitutedC₁-C₃ alkoxy group, one or more spirocyclic groups where R₃ is linked toR₄, R₅ is linked to R₆ or R₈ is linked to R₇, or R₂ is linked to R₈ toform a C₃-C₄ cycloalkyl ring; andR₇ represents a hydrogen atom, cyano, an optionally substituted C₁-C₃alkyl, an optionally substituted C₁-C₃ alkoxy group or an optionallysubstituted aryl or heteroaryl ring, or is linked to R₈ to form aspirocyclic group.

In formula (I) defined herein, the R₁ heteroaryl ring may be attacheddirectly to the amide nitrogen atom to form an N-aryl bond. The arylring may be monocyclic or bicyclic. Where the ring is bicyclic, thesecond ring may be aromatic, or may be partly saturated, and thus notevery atom in the 5-10 membered heteroaryl ring need be in an arylsystem, there must be at least one heteroaryl ring within the 5-10atoms.

In one embodiment R₁ represents a 5 to 10 membered (e.g. 5, 6, 7, 8, 9or 10 membered) heteroaryl ring which may be optionally substituted withone or more (e.g. one, two, three or four) of -Q₁-(R₉)_(n).

In a another embodiment R₁ represents a 5 or 6 membered heteroaryl ringwhich may be optionally substituted with one or more (e.g. one, two,three or four) of -Q₁-(R₉), In a further embodiment R₁ represents 9membered bicyclic heteroaryl ring which may be optionally substitutedwith one or more (e g one, two, three or four) of -Q₁-(R₉).

The heteroaryl ring of R₁ may be monocyclic or bicyclic and comprise oneor more (e.g. 1, 2 or 3) heteroatoms independently selected fromnitrogen, oxygen and sulphur.

In one embodiment the optionally substituted 5 to 10 membered heteroarylring of R₁ is selected from thiazolyl, pyridinyl, isoxazolyl,thiadiazolyl, indazolyl, imidazolyl, benzimidazolyl, benzothiazolyl,pyrazolyl, pyridazinyl, pyrimidinyl, naphthyridinyl, isoquinolinyl,pyrazinyl, tetrahydrothiazolopyridinyl, imidazopyridinyl, triazolyl,pyrazolopyridinyl, tetrahydropyrazolopyrazinyl,tetrahydrothiazoloazepinyl, thiazolopyridinyl

The 5 to 10 membered heteroaryl ring of R₁ may be selected fromthiazolyl, pyridinyl, isoxazolyl, thiadiazolyl, indazolyl, imidazolyl,benzimidazolyl, benzothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,naphthyridinyl, isoquinolinyl, pyrazinyl, tetrahydrothiazolopyridinyl,imidazopyridinyl, triazolyl, and pyrazolopyridinyl.

In a further embodiment the 5 to 10 membered heteroaryl ring of R₁ isselected from thiazolyl, imidazolyl, benzothiazolyl, pyrazolyl,imidazopyridinyl and tetrahydrothiazolopyridinyl, pyridinyl,tetrahydropyrazolopyrazinyl, pyrimidinyl, isoquinolinyl,pyrazolopyridinyl, pyridazinyl, tetrahydrothiazoloazeptine, phenyl,thiazolopyridinyl, and indazolyl.

The 5 to 10 membered heteroaryl ring of R₁ may be selected fromthiazolyl, imidazolyl, benzothiazolyl, pyrazolyl, imidazopyridinyl andtetrahydrothiazolopyridinyl.

In a further embodiment the 5 to 10 membered heteroaryl ring of R₁ isselected from thiazolyl and imidazolyl.

Typical examples of the 5 to 10 membered heteroaryl ring of R₁ includethiazol-2-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, thiadiazol-2-yl,isoxazol-5-yl, indazol-5-yl, benzoimidazol-5-yl, benzonthiazol-2-yl,pyrazol-5-yl, pyrazol-3-yl, pyrimidin-5-yl, pyrimidin-4-ylpyridazin-3-yl, imidazol-4-yl, 1,8-napthylridin-2-yl,imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-6-yl,imidazo[1,2-a]pyridin-5-yl, pyrazin-2-yl, thiazolo[5,4-c]pyridine-2-yl,imidazo-4-yl, 1,2,3-triazol-4-yl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-yl,5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-yl,thiazolo[4,5-b]pyridine-2-yl, thiazolo[4,5-c]pyridine-2-yl,tetrahydropyrazolo[1,5-a]pyrazin-2-yl, pyrazolo[1,5-a]pyridine-2-yl,quinolin-3-yl, isoquinolin-3-yl, benzo[d]thiazol-2-yl.

The group R₁ may be further substituted. R₁ may represent a 5 to 10membered heteroaryl ring substituted with one or more of Q₁-(R₉)_(n),wherein

n is 0 or 1; Q₁ represents a hydrogen atom, a halogen atom, cyano, acovalent bond, —NR₁₀—, —CONR₁₀—, —NR₁₀CO—, an oxygen atom, oxo, nitro,—S(O)_(m)—, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, —CO—,—SO₂R₁₁, —NR₁₁R₁₂, —NR₁₁COR₁₂, —NR₁₀CONR₁₁R₁₂, —CONR₁₁R₁₂, —CO₂R₁₁,—NR₁₁CO₂R₁₂, —SO₂NR₁₁R₁₂, —CONR₁₁, —C(O)R₁₁, —NR₁₁SO₂R₁₂, NR₁₁SO₂NR₁₃R₁₄and SO₂NR₁₁ or an optionally substituted C₁-C₆ alkylene, —C₂-C₆alkenylene or —C₁-C₆ alkyl group;m is 0, 1 or 2;R₁₀, R₁₁ and R₁₂ each independently represent a hydrogen atom or anoptionally substituted C₁-C₆ alkyl or optionally substituted C₁-C₆alkylene group.

When n is 1, R₉ represents an optionally substituted 3 to 10 memberedheterocyclyl, heteroaryl, aryl or cycloalkyl ring. (When n is 0, Q ispresent and R₉ is absent).

R₉ may be optionally substituted with one or more substituents selectedfrom halogen, optionally substituted C₁-C₆ haloalkyl, optionallysubstituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, oxo, cyano, nitro, optionallysubstituted heterocyclyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted aryl, -Q₂-NR₁₃CONR₁₄R₁₅,-Q₂-NR₁₃R₁₄, -Q₂-NR₁₃COR₁₄, -Q₂-COR₁₃, -Q₂-SO₂R₁₃, -Q₂-CONR₁₃,Q₂-CONR₁₃R₁₄, -Q₂-CO₂R₁₃, -Q₂-SO₂NR₁₃R₁₄, -Q₂-NR₁₃SO₂R₁₄ and-Q-NR₁₃SO₂NR₁₄R₁₅; wherein

Q₂ represents a covalent bond or a C₁-C₆ alkylene or C₂-C₆ alkenylenegroup; andR₁₃, R₁₄ and R₁₅ each independently represent hydrogen or an optionallysubstituted C₁-C₆ alkyl, or an optionally substituted heterocyclyl, oran optionally substituted heteroaryl, or an optionally substituted aryl,or an optionally substituted cycloalkyl.

Alternatively R₉ may be substituted with further optionally substituted3 to 10 membered heterocyclyl, heteroaryl, aryl or cycloalkyl rings,either directly attached or via linking group. The linking group may bean oxygen, a carbonyl, an optionally substituted C₁-C₆ alkylene or anoptionally substituted C₁-C₆ alkyleneoxy chain. The linking group may beoxygen, —CO—, a C₁-C₆ alkylene group or a C₁-C₆ alkyleneoxy group. Inone embodiment the linking group may be a carbonyl, or an alkylenechain, for example, —CO— or a C₁-C₆ alkylene group.

In one embodiment R₂ represents C₁-C₆ alkyl. In one embodiment R₂represents C₁-C₄ alkyl. In one embodiment R₂ represents C₁-C₃ alkyl. Inone embodiment R₂ represents C₁-C₂ alkyl. In one embodiment R₂represents C₁-C₃ alkoxy. In one embodiment R₂ represents C₁-C₂ alkoxy.In one embodiment R₂ represents cyano. In one embodiment R₂ representsmethyl. In one embodiment R₂ represents substituted methyl. In oneembodiment R₂ represents CH₂X where X is OMe, F or Cl. In one embodimentR₂ represents methoxy. In one embodiment R₂ represents C₁-C₆ alkyl,C₁-C₄ alkyl, C₁-C₃ alkyl or C₁-C₂ alkyl, C₁-C₃ alkoxy, C₁-C₂ alkoxy,cyano, methyl or substituted methyl and R₃, R₄, R₅, R₆, R₇ and R₈ eachindependently represent a hydrogen atom.

In another embodiment R₃ represents C₁-C₆ alkyl. In another embodimentR₃ represents C₁-C₄ alkyl. In another embodiment R₃ represents C₁-C₃alkyl. In another embodiment R₃ represents C₁-C₂ alkyl (e.g. methyl orethyl). In another embodiment R₃ represents C₁-C₆ alkyl, C₁-C₄ alkyl,C₁-C₃ alkyl or C₁-C₂ alkyl (e.g. methyl or ethyl) and R₁, R₂, R₄, R₅,R₆, R₇ and R₈ each independently represent a hydrogen atom.

In an alternative embodiment R₃ is linked to R₄ to form a spirocyclicgroup. The spirocyclic group may be made of carbon atoms, or may containone or more heteroatoms. The spirocyclic group can contain 3, 4, 5 or 6atoms, i.e. a C₃-C₆ spirocyclic group. The spirocyclic groups can beoptionally further substituted.

In an alternative embodiment R₅ is linked to R₆ to form a spirocyclicgroup. The spirocyclic group may be made of carbon atoms, or may containone or more heteroatoms. The spirocyclic group can contain 3, 4, 5 or 6atoms, i.e. a C₃-C₆ spirocyclic group. The spirocyclic groups can beoptionally further substituted.

In a further embodiment R₂ represents methyl or methoxy. In oneembodiment R₂ represents methyl or methoxy and R₃, R₄, R₅, R₆, R₇ and R₈each independently represent a hydrogen atom. In a further embodiment R₂represents methyl. In one embodiment R₂ represents methyl and R₃, R₄,R₅, R₆, R₇ and R₈ each independently represent a hydrogen atom.

In a further embodiment when R₂ is other than hydrogen, R₃ is hydrogen.When R₃ is other than hydrogen, R₂ is hydrogen such that either R₂ or R₃must be H.

In a further embodiment R₂ is linked to R₈ to form a C₃-C₄ cycloalkylring. The cycloalkyl ring may be cyclopropyl or cyclobutyl.

In a further embodiment R₇ represents a hydrogen atom, a fluorine atom,cyano, an optionally substituted C₁-C₃ alkyl, an optionally substitutedC₁-C₃ alkoxy group or an optionally substituted aryl or heteroaryl ring.In a still further embodiment R₇ represents a hydrogen atom, cyano, anoptionally substituted C₁-C₃ alkyl, an optionally substituted C₁-C₃alkoxy group or an optionally substituted aryl or heteroaryl ring. R₇can represent H, methyl or substituted methyl. R₇ may be methyl. R₇ maybe CF₃. R₇ can represent an optionally substituted aryl or heteroarylring. R₇ can represent an optionally substituted phenyl, pyridyl orpyrimidyl ring. R₇ can represent an optionally substituted phenyl orpyridyl ring.

In an alternative embodiment R₇ is linked to R₈ to form a spirocyclicgroup. The spirocyclic group may be made of carbon atoms, or may containone or more heteroatoms. The spirocyclic group can contain 3, 4, 5 or 6atoms. The spirocyclic groups can be optionally further substituted.

In an alternative embodiment, R₇ is linked to R % to form a C₃-C₄cycloalkyl ring, i.e. cyclopropyl or cyclobutyl. In one embodiment, R₇and 1% together form a cyclopropyl ring.

The C₃-C₄ cycloalkyl rings disclosed herein with respect to R₂, R₆, R₇and R₈ may be optionally substituted with halo, deutero, C₁₋₃ alkyl,C₁₋₃ alkoxy, cyano, amino, nitro or SF₅.

Q₁ represents a hydrogen atom, a halogen atom, cyano, a covalent bond,—NR₁₀—, —CONR₁₀—, —NR₁₀CO—, an oxygen atom, oxo, nitro, —S(O)_(m)—,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, —CO—, —SO₂R₁₁,—NR₁₁R₁₂, —NR₁₁COR₁₂, —NR₁₀CONR₁₁R₁₂, —CONR₁₁R₁₂, —CO₂R₁₁, —NR₁₁CO₂R₁₂,—SO₂NR₁₁R₁₂, —CONR₁₁, —C(O)R₁₁, —NR₁₁SO₂R₁₂, NR₁₁SO₂NR₁₃R₁₄ and SO₂NR₁₁or an optionally substituted C₁-C₆ alkylene, —C₂-C₆ alkenylene or —C₁-C₆alkyl group;

In one embodiment Q₁ represents a hydrogen atom, a halogen atom, cyano,a covalent bond, —NR₁₀—, —CONR₁₀—, —NR₁₀CO—, an oxygen atom, —S(O)_(m)—,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, —CO—, —SO₂R₁₁,—NR₁₁R₁₂, —NR₁₁COR₁₂, —NR₁₀CONR₁₁R₁₂, —CONR₁₁R₁₂, —CO₂R₁₁, —NR₁₁CO₂R₁₂,—SO₂NR₁₁R₁₂, —CONR₁₁, —C(O)R₁₁ and —NR₁₁SO₂R₁₂ or an optionallysubstituted C₁-C₆ alkylene, —C₂-C₆ alkenylene or —C₁-C₆ alkyl group. Forexample, Q₁ may be selected from a halogen atom, hydrogen atom, acovalent bond, NR₁₀ a C₁-C₆ alkylene or C₂-C₆ alkenylene group which maybe optionally substituted with hydroxy, a halogen atom, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl,—COR₁₁, —SO₂R₁₁, —NR₁₁R₁₂, —NR₁₁COR₁₂, —CONR₁₁R₁₂, —CO₂R₁₁, —NR₁₁CO₂R₁₂,—SO₂NR₁₁R₁₂—C(O)N, —C(O) and —NR₁₁SO₂R₁₂.

In another embodiment Q₁ may be selected from a hydrogen atom, acovalent bond, NR₁₀ or a C₁-C₆ alkylene, —C₁-C₄ alkylene, C₁-C₂alkylene, C₂-C₆ alkenylene or C₂-C₄ alkenylene group which may beoptionally substituted with hydroxy, a halogen atom (e.g. fluorine,chlorine or bromine), C₁-C₆ alkyl, C₁-C₄ alkyl, C₁-C₂ alkyl, C₁-C₆haloalkyl, C₁-C₄ haloalkyl, C₁-C₂ haloalkyl, C₁-C₆ alkoxy, C₁-C₄ alkoxy,C₁-C₂ alkoxy, C₁-C₆ haloalkoxy, C₁-C₄ haloalkoxy, C₁-C₂ haloalkoxy,—C₁-C₆ hydroxyalkyl, C₁-C₄ hydroxyalkyl, C₁-C₂ hydroxyalkyl, —COR₁₁,—SO₂R₁₁, —NR₁₁R₁₂, —NR₁₁COR₁₂, —CONR₁₁R₁₂, —CO₂R₁₁, —NR₁₁CO₂R₁₂,—SO₂NR₁₁R₁₂ and —NR₁₁SO₂R₁₂.

In a further embodiment Q₁ may be selected from a covalent bond, NR₁₀(e.g. methyamino), —C₁-C₄ alkylene (e.g. methylene or ethylene) or aC₂-C₄ alkenylene (e.g. vinyl) group which may be optionally substitutedwith hydroxy, a halogen atom (e.g. fluorine, bromine or chlorine), C₁-C₄alkyl (e.g. propyl, isobutyl or tert butyl), C₁-C₂ alkyl (e.g. methyl orethyl), C₁-C₂ haloalkyl (e.g. trifluoromethyl), C₁-C₂ alkoxy (e.g.methoxy or methoxymethyl), C₁-C₂ haloalkoxy (e.g. trifluoromethoxy),C₁-C₂ hydroxyalkyl (e.g. hydroxymethyl or hydroxyethyl), —COR₁₁ (e.g.acetyl), —SO₂R₁₁ (e.g. methylsulphonyl) —NR₁₁R₁₂ (e.g. amino orN,N-dimethylamino), —NR₁₁COR₁₂ (e.g. N-acetyl), —CONR₁₁R₁₂ (e.g. amido),—CO₂R₁₁ (e.g. methoxycarbonyl or ethoxycarbonyl), —NR₁₁CO₂R₁₂,—SO₂NR₁₁R₁₂ (e.g. dimethylaminosulphonyl) and —NR₁₁SO₂R₁₂.

In a further embodiment Q₁ may be selected from a halogen atom (e.g.bromine, chlorine or fluorine), C₁-C₄ alkyl (e.g. propyl or tert butyl),C₁-C₂ alkyl (e.g. methyl or ethyl), C₁-C₂ haloalkyl (e.g.trifluoromethyl), C₁-C₂ alkoxy (e.g. methoxy), —COR₁₁ (e.g. acetyl),—SO₂R₁₁ (e.g. methylsulphonyl), cyano, CONR₁₁R₁₂ and C₁-C₂ haloalkoxy(e.g. trifluoromethoxy).

In a further embodiment Q₁ may be selected from a halogen atom (e.g.bromine or chlorine), C₁-C₄ alkyl (e.g. propyl or tert butyl), C₁-C₂alkyl (e.g. methyl or ethyl), C₁-C₂ haloalkyl (e.g. trifluoromethyl),C₁-C₂ alkoxy (e.g. methoxy), —COR₁₁ (e.g. acetyl) and —SO₂R₁₁ (e.g.methylsulphonyl).

In one embodiment Q₂ may be selected from a hydrogen atom, a covalentbond or an optionally substituted C₁-C₆ alkylene (e.g. C₁-C₃ alkylene,C₁-C₄ alkylene, C₁-C₂ alkylene, C₂-C₆ alkenylene, C₂-C₄ alkenylene.

In another embodiment Q₂ may be selected from a hydrogen atom, acovalent bond, C₁-C₂ alkylene (e.g. methylene, ethylene), C₂-C₄alkenylene (e.g. ethenylene).

In a further embodiment Q₂ is selected from H, a covalent bond,methylene and ethylene.

When n is 0, Q₁ may be selected from a hydrogen atom, a halogen atom,optionally substituted C₁-C₆ alkyl, COR₁₁, —SO₂R₁₁, —C(O)NR₁₁R₁₂,optionally substituted C₁-C₆ alkoxy, C₁-C₆ haloalkyl and C₁-C₆haloalkoxy, wherein R₁₁ and R₁₂ are as defined above.

Optionally, when n is 0, Q₁ may be selected from a hydrogen atom, ahalogen atom, C₁-C₆ alkyl, COR₁₁ or —SO₂R₁₁, wherein R₁₁ is as definedabove.

Alternatively, when n is 1 Q₁ may be selected from a covalent bond,—CO—, a C₁-C₆ alkylene or C₂-C₆ alkenylene group which may be optionallysubstituted with hydroxy and —NR₁₀.

In one embodiment n is 1 In one embodiment R₉ represents a 3 to 10membered (e.g. 3, 4, 5, 6, 7, 8, 9 or 10 membered) heterocyclyl,heteroaryl or cycloalkyl ring which may be optionally substituted withone or more substituents selected from halogen, optionally substitutedC₁-C₆ haloalkyl, optionally substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, oxo, cyano, nitro,heterocyclyl, -Q₂-NR₁₃CONR₁₄R₁₅, -Q₂-NR₁₃R₁₄, -Q₂-NR₁₃COR₁₄, -Q₂-COR₁₃,-Q₂-SO₂R₁₃, -Q₂-CONR13R₁₄, -Q₂-CO₂R₁₃, -Q₂-SO₂NR₁₃R₁₄, -Q₂-NR₁₃SO₂R₁₄and -Q₂-NR₁₃SO₂R₁₄R₁₅.

In one embodiment R₉ represents a 3 to 10 membered (e.g. 3, 4, 5, 6, 7,8, 9 or 10 membered) heterocyclyl, heteroaryl or cycloalkyl ring whichmay be optionally substituted with one or more (e.g. one, two or three)substituents selected from a halogen atom (e.g. fluorine, bromine orchlorine), C₁-C₆ haloalkyl, C₁-C₄ haloalkyl, C₁-C₂ haloalkyl, C₁-C₆alkoxy, C₁-C₄ alkoxy, C₁-C₂ alkoxy, C₁-C₆ haloalkoxy, C₁-C₄ haloalkoxy,C₁-C₂ haloalkoxy, C₁-C₆ alkyl, C₁-C₄ alkyl, C₁-C₂ alkyl, C₂-C₆ alkenyl,C₂-C₄ alkenyl, C₁-C₆ hydroxyalkyl, oxo, cyano, -Q₂-NR₁₃CONR₁₄,-Q₂-NR₁₃R₁₄, -Q₂-NR₁₃SO₂R₁₄, -Q₂-NR₁₃COR₁₄, -Q₂-COR₁₃, -Q₂-SO₂R₁₃,-Q₂-CONR₁₃, -Q₂-CO₂R₁₃, -Q₂-SO₂NR₁₃R₁₄ and -Q₂-NR₁₃SO₂R₁₄.

In another embodiment R₉ represents a 3 to 10 membered (e.g. 3, 4, 5, 6,7, 8, 9 or 10 membered) heterocyclyl, heteroaryl, aryl or cycloalkylring which may be optionally substituted with one or more (e.g. one, twoor three) substituents selected from a halogen atom (e.g. fluorine,bromine or chlorine), C₁-C₂ alkoxy (e.g. methoxy, methoxymethyl), C₁-C₄alkyl (e.g. methyl, ethyl, propyl, tert butyl), oxo, cyano,-Q₂-NR₁₃CONR₁₄ (e.g. acetamido, acetamidomethyl), -Q₂-NR₁₃R₁₄ (e gamino), -Q₂-NR₁₃SO₂R₁₁ (e g methylsulphonylamino), -Q₂-SO₂R₁₃ (e.g.methylsulphonyl) or a further optionally substituted 3 to 10 memberedheterocyclyl, heteroaryl, aryl or cycloalkyl ring.

In another embodiment R₉ represents a 3 to 10 membered (e.g. 3, 4, 5, 6,7, 8, 9 or 10 membered) heterocyclyl, aryl, heteroaryl or cycloalkylring such as morpholinyl, piperidinyl, pyrrolidinyl, diazepanyl,piperazinyl, pyridazinyl, pyrazinyl, pyrazolyl, cyclopropyl, cyclohexyl,cyclopentyl, pyridinyl, imidazolyl, indolinyl, isoindolinyl,pyrimidinyl, isoxazolyl, dihydroindenyl, dihydroisoquinolinyl,tetrahydropyranyl, phenyl, oxadiazolyl, triazolyl, isoquinolinyl,indazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazolpyridinyl,imidazopyrimidinyl, imidazopyrazinyl, oxazolyl and quinolinyl, which maybe optionally substituted. R₉ may be optionally substituted with one ormore (e.g. one, two or three) substituents selected from a halogen atom(e.g. fluorine, bromine or chlorine), optionally substituted C₁-C₃alkoxy(e.g. methoxy, methoxymethyl), optionally substituted C₁-C₄alkyl (e.g.methyl, ethyl, propyl, tert butyl), oxo, cyano, -Q₂-NR₁₃CONR₁₄ (e.g.acetamido, acetamidomethyl), -Q₂-NR₁₃R₁₄ (e.g. amino), -Q₂-NR₁₃SO₂R₁₄(e.g. methylsulphonylamino), -Q₂-SO₂R₁₃ (e.g. methylsulphonyl),-Q₂-SO₂NR₁₃R₁₄, and -Q₂-CONR₁₃R₁₄.

In yet another embodiment R₉ represents a 3 to 10 membered (e.g. 3, 4,5, 6, 7, 8, 9 or 10 membered) heterocyclyl, aryl, heteroaryl orcycloalkyl ring such as morpholinyl, piperidinyl, pyrrolidinyl,diazepanyl, piperazinyl, pyridazinyl, pyrazinyl, pyrazolyl, cyclopropyl,cyclohexyl, cyclopentyl, pyridinyl, imidazolyl, indolinyl, isoindolinyl,pyrimidinyl, isoxazolyl, dihydroindenyl, dihydroisoquinolinyl,tetrahydropyranyl, phenyl, oxadiazolyl and triazolyl, which may beoptionally substituted. R₉ may be optionally substituted with one ormore (e.g. one, two or three) substituents selected from a halogen atom(e.g. fluorine, bromine or chlorine), C₁-C₂alkoxy (e.g. methoxy,methoxymethyl), C₁-C₄alkyl (e.g. methyl, ethyl, propyl, tert butyl),oxo, cyano, -Q₂-NR₁₃CONR₁₄ (e.g. acetamido, acetamidomethyl),-Q₂-NR₁₃R₁₄ (e.g. amino), -Q₂-NR₁₃SO₂R₁₄ (e.g. methylsulphonylamino),-Q₂-SO₂R₁₃ (e.g. methyl sulphonyl).

In another embodiment R₉ represents a 3 to 10 membered (e.g. 3, 4, 5, 6,7, 8, 9 or 10 membered) heterocyclyl, aryl, heteroaryl or cycloalkylring such as phenyl, morpholinyl, piperidinyl, pyrrolidinyl, diazepanyl,piperazinyl, cyclopropyl, cyclohexyl, cyclopentyl, pyridinyl,imidazolyl, indolinyl, pyrimidinyl, isoxazolyl, quinolinyl, triazolyl,isoquinolinyl, indazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl,imidazolpyridinyl, imidazopyrimidinyl, imidazopyrazinyl, oxazolyl andquinolinyl, which may be optionally substituted with one or more (e.g.one, two or three) substituents selected from a halogen atom,C₁-C₆alkoxy, C₁-C₆alkyl, oxo, cyano, -Q₂-NR₁₃CONR₁₄, -Q₂-NR₁₃R₁₄,-Q₂-NR₁₃SO₂R₁₄, -Q₂-SO₂NR₁₃R₁₄, and -Q₂-CONR₁₃R₁₄.

In another embodiment R₉ represents a 3 to 10 membered (e.g. 3, 4, 5, 6,7, 8, 9 or 10 membered) heterocyclyl, aryl, heteroaryl or cycloalkylring such as phenyl, morpholinyl, piperidinyl, pyrrolidinyl, diazepanyl,piperazinyl, cyclopropyl, cyclohexyl, cyclopentyl, pyridinyl,imidazolyl, indolinyl, pyrimidinyl, isoxazolyl, quinolinyl, triazolyl,which may be optionally substituted with one or more (e.g. one, two orthree) substituents selected from a halogen atom, C₁-C₆alkoxy,C₁-C₆alkyl, oxo, cyano, -Q₂-NR₁₃CONR₁₄, -Q₂-NR₁₃R₁₄ and -Q₂-NR₁₃SO₂R₁₄.

In a further embodiment, R₉ represents an optionally substituted 5 or 6membered monocyclic heterocyclyl, aryl, heteroaryl or cycloalkyl ring.In another embodiment, R₉ represents an optionally substituted 9 or 10membered bicyclic heterocyclyl, aryl, heteroaryl or cycloalkyl ring.

In an even further embodiment R₉ represents an optionally substituted 6membered heterocyclyl, aryl, heteroaryl or cycloalkyl ring.

Typical examples of the 3 to 10 membered heterocyclyl, aryl, heteroarylor cycloalkyl ring of R₉ include piperidin-1-yl, indolin-1-yl,indolin-2-yl, piperazin-1-yl, pyrrolidin-1-yl,3,4-dihydroisoquinolin-2(1H)-yl, phenyl, pyridin-2,3,4-yl,imidazol-1-yl, isoxazol-4-yl, pyrimidin-4-yl, 1H-1,2,3-triazol-2-yl,thiazol-2-yl, thiazolyl, cyclohexyl cyclopropyl, indazol-5-yl,indozol-4-yl, pyrazolo[1,5-a]pyrimidin-7-yl,imidazo[1,2-a]pyrimidin-5-yl, imidazo[1,2-a]pyridin-5-yl,imidazo[1,2-a]pyrazine-6-yl, imidazo[1,2-a]pyrimidin-6-yl, oxazol-5-yl,pyrazol-4-yl, isoxazol-4-yl, imidazole-4-yl and quinolin-4-yl.

In certain embodiments R₉ is selected from substituted or unsubstitutedphenyl, morpholinyl, isoxazolyl, pyridinyl, piperazinyl, cyclopropyl,indolinyl, pyrrolidinyl, isoquinolinyl, indazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, imidazolpyridinyl, imidazopyrimidinyl,imidazopyrazinyl, oxazolyl and quinolinyl.

In certain embodiments R₉ is selected from substituted or unsubstitutedphenyl, morpholinyl, isoxazolyl, pyridinyl, piperazinyl, cyclopropyl,indolinyl and pyrrolidinyl.

In certain embodiments R₉ is substituted or unsubstituted phenyl.

In one embodiment m is 1 or 2, preferably 2.

In another embodiment R₁₀, R₁₁ and R₁₂ each independently representhydrogen or optionally substituted C₁-C₆ alkyl. C₁-C₆ alkyl may besubstituted with one or more halogen, e.g. fluorine.

In another embodiment R₁₀, R₁₁ and R₁₂ each independently representhydrogen, C₁-C₆ alkyl, C₁-C₄ alkyl or C₁-C₂ alkyl.

In another embodiment R₁₀, R₁₁ and R₁₂ each independently representhydrogen or C₁-C₂ alkyl (e.g. methyl or ethyl).

R₁₀, R₁₁ and R₁₂ can each independently represent an optionallysubstituted C₁-C₆ alkylene group which acts a linking moiety to afurther ring.

R₁₃, R₁₄ and R₁₅ each independently represent hydrogen or an optionallysubstituted C₁-C₆ alkyl, or an optionally substituted heterocyclyl, oran optionally substituted heteroaryl, or an optionally substituted aryl,or an optionally substituted cycloalkyl. R₁₃, R₁₄ and R₁₅ may eachindependently represent hydrogen or C₁-C₃ alkyl.

In a further embodiment n is 0 and R₁ may be optionally substituted byone or more (e.g. one, two, three or four) Q₁ substituents independentlyselected from a halogen atom (e.g. bromine, chlorine or fluorine), C₁-C₄alkyl (e.g. propyl or tert butyl), C₁-C₂ alkyl (e.g. methyl or ethyl),C₁-C₂ haloalkyl (e.g. trifluoromethyl), C₁-C₂ alkoxy (e.g. methoxy),—COR₁₁ (e.g. acetyl), —SO₂R₁₁ (e g methylsulphonyl), cyano, CONR₁₁R₁₂and C₁-C₂ haloalkoxy.

In a further embodiment n is 0 and R₁ may be optionally substituted byone or more (e.g. one, two, three or four) Q₁ substituents independentlyselected from a halogen atom (e.g. bromine or chlorine), C₁-C₄ alkyl(e.g. propyl or tert butyl), C₁-C₂ alkyl (e.g. methyl or ethyl), C₁-C₂haloalkyl (e.g. trifluoromethyl), C₁-C₂ alkoxy (e.g. methoxy), —COR₁₁(e.g. acetyl) and —SO₂R₁₁ (e.g. methylsulphonyl).

In one embodiment n is 0 and R₁ represents a 5 or 6 membered heteroarylring which may be optionally substituted with one or more (e.g. one,two, three or four) Q₁ substituents independently selected from ahalogen atom (e.g. fluorine, bromine or chlorine), C₁-C₄ alkyl (e.g.propyl, isobutyl or tert butyl), C₁-C₂ alkyl (e.g. methy or ethyl),C₁-C₂ haloalkyl (e.g. trifluoromethyl), C₁-C₂ alkoxy (e.g. methoxy ormethoxymethy), C₁-C₂ haloalkoxy (e.g. trifluoromethoxy), C₁-C₂hydroxyalkyl (e.g. hydroxymethyl or hydroxyethyl), —COR₁₁ (e.g. acetyl),—SO₂R₁₁ (e.g. methylsulphonyl), —NR₁₁R₁₂ (e.g. amino orN,N-dimethylamino), —NR₁₁COR₁₂ (e.g. N-acetyl), —CONR₁₁R₁₂ (e.g. amido),—CO₂R₁₁ (e.g. methoxycarbonyl or ethoxycarbonyl), —NR₁₁CO₂R₁₂,—SO₂NR₁₁R₁₂ (e.g. dimethylaminosulphonyl) and —NR₁₁SO₂R₁₂;

In another embodiment n is 0 and R₁ represents 9 membered heteroarylring which may be optionally substituted with one or more (e.g. one,two, three or four) Q₁ substituents independently selected from ahalogen atom (e.g. fluorine, bromine or chlorine), C₁-C₄ alkyl (e.g.propyl, isobutyl or tert butyl), C₁-C₂ alkyl (e.g. methy or ethyl),C₁-C₂ haloalkyl (e.g. trifluoromethyl), C₁-C₂ alkoxy (e.g. methoxy ormethoxymethy), C₁-C₂ haloalkoxy (e.g. trifluoromethoxy), C₁-C₂hydroxyalkyl (e.g. hydroxymethyl or hydroxyethyl), —COR₁₁ (e.g. acetyl),—SO₂R₁₁ (e.g. methylsulphonyl) —NR₁₁R₁₂ (e.g. amino orN,N-dimethylamino), —NR₁₁COR₁₂ (e.g. N-acetyl), —CONR₁₁R₁₂ (e.g. amido)—CO₂R₁₁ (e.g. methoxycarbonyl or ethoxycarbonyl), —NR₁₁CO₂R₁₂,—SO₂R₁₁R₁₂ (e.g. dimethylaminosulphonyl) and —NR₁₁SO₂R₁₂;

In another embodiment n is 0 and R₁ represents 9 membered heteroarylring which may be optionally substituted with one or more (e.g. one,two, three or four) Q₁ substituents independently selected from ahalogen atom (e.g. fluorine, bromine or chlorine), cyano, C₁-C₁ alkyl (eg propyl, isobutyl or tert butyl), C₁-C₂ alkyl (e.g. methy or ethyl),C₁-C₂ haloalkyl (e.g. trifluoromethyl), C₁-C₂ alkoxy (e.g. methoxy ormethoxymethy), C₁-C₂ haloalkoxy (e.g. trifluoromethoxy), C₁-C₂hydroxyalkyl (e.g. hydroxymethyl or hydroxyethyl), —COR₁₁ (e.g. acetyl),—SO₂R₁₁ (e.g. methylsulphonyl) —NR₁₁R₁₂ (e.g. amino orN,N-dimethylamino), —NR₁₁COR₁₂ (e.g. N-acetyl), —CONR₁₁R₁₂ (e.g. amido)—CO₂R₁₁ (e.g. methoxycarbonyl or ethoxycarbonyl), —NR₁₁CO₂R₁₂,—SO₂NR₁₁R₁₂ (e.g. dimethylaminosulphonyl) and —NR₁₁SO₂R₁₂;

Compounds of the disclosure may have a nitrogen atom in the orthoposition with respect to the carbon atom attached to the amide nitrogen.In such instances R₁ has an ortho nitrogen atom to form compoundsincluding the moiety N—C—NH—CO; as represented by the Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:Y represents the remaining atoms of a 5 or 6 membered heteroaryl ringwhich may optionally substituted or fused with further ring which may befurther optionally substituted;R₂, R₃, R₄, R₅, R₆ and R₈ each independently represent a hydrogen atom,cyano, an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₁-C₆ alkoxy group, one or more spirocyclic groups where R₃ is linked toR₄, R₅ is linked to R₆ or R₈ is linked to R₇, or R₂ is linked to R₈ toform an optionally substituted C₃-C₄ cycloalkyl ring, or R₆ is linked toR₇ to form an optionally substituted C₃-C₄ cycloalkyl ring; andR₇ represents a hydrogen atom, a fluorine atom, cyano, an optionallysubstituted C₁-C₃ alkyl, an optionally substituted C₁-C₃ alkoxy group oran optionally substituted aryl or heteroaryl ring or is linked to R₈ toform a spirocyclic group, or is linked to R₆ to form an optionallysubstituted C₃-C₄ cycloalkyl ring.

In one embodiment, Y represents the remaining atoms of a 5 or 6 memberedheteroaryl ring which may optionally substituted or fused with furtherring which may be further optionally substituted;

R₂, R₃, R₄, R₅, R₆ and R₈ each independently represent a hydrogen atom,cyano, an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₁-C₆ alkoxy group, one or more spirocyclic groups where R₃ is linked toR₄, R₅ is linked to R₆ or R₈ is linked to R₇, or R₂ is linked to R₈ toform a C₃-C₄ cycloalkyl ring; andR₇ represents a hydrogen atom, cyano, an optionally substituted C₁-C₃alkyl, an optionally substituted C₁-C₃ alkoxy group or an optionallysubstituted aryl or heteroaryl ring or is linked to R₈ to form aspirocyclic group.

The moiety symboloised by Y may be substituted according to Q₁-(R₉)_(n)as defined herein.

Examples of R₁ include those shown below:

Examples of compounds of the invention include:

-   (S)-1-cyano-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(3-fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(2-fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   N-(5-(4-chlorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   N-(5-(3-chlorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   N-(5-(2-chlorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(5-methylthiazol-2-yl)pyrrolidine-3-carboxamide-   N-(5-(tert-butyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(2-phenylthiazol-5-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-phenyl-1,3,4-thiadiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(3-phenylisoxazol-5-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(3-(4-methoxyphenyl)isoxazol-5-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-phenylisoxazol-3-yl)pyrrolidine-3-carboxamide-   N-(5-(tert-butyl)isoxazol-3-yl)-1-cyanopyrrolidine-3-carboxamide-   N-(3-(tert-butyl)-1H-pyrazol-5-yl)-1-cyanopyrrolidine-3-carboxamide-   N-(benzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(6-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(6-methoxybenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   N-(6-bromobenzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   N-(1H-benzo[d]imidazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(pyridin-2-yl)pyrrolidine-3-carboxamide-   N-(5-chloropyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(5-methylpyridin-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-methoxypyridin-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-morpholinopyridin-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(piperidin-1-yl)pyridin-2-yl)pyrrolidine-3-carboxamide-   N-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(4-phenylpyridin-2-yl)pyrrolidine-3-carboxamide-   N-([2,3′-bipyridin]-6′-yl)-1-cyanopyrrolidine-3-carboxamide-   N-([3,3′-bipyridin]-6-yl)-1-cyanopyrrolidine-3-carboxamide-   N-([3,4′-bipyridin]-6-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(6-phenylpyridin-3-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(6-phenylpyridazin-3-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(2-phenylpyrimidin-5-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-cyclohexylpyridin-2-yl)pyrrolidine-3-carboxamide-   N-(1-benzyl-1H-indazol-5-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(1-propyl-1H-benzo[d]imidazol-5-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-m    ethylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(7-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(4-bromobenzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(7-bromoimidazo[1,2-a]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(pyrazolo[1,5-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-methoxypyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-phenylpyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-phenylpyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1,8-naphthyridin-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-benzylthiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(isoquinolin-3-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-methyl-5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(4-methoxypiperidin-1-yl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(6-(1H-1,2,3-triazol-1-yl)benzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(6-(2H-1,2,3-triazol-2-yl)benzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-(methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-methyl-5-(morpholinomethyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(3,4-difluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(pyridin-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(pyridin-2-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (R)-1-cyano-N-(5-phenylpyridin-2-yl)pyrrolidine-3-carboxamide-   (2S,3S)-1-cyano-2-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   (2S,3S)-1-cyano-N-(5-(4-fluorophenyl)thiazol-2-yl)-2-methylpyrrolidine-3-carboxamide-   (2S,3S)-1-cyano-2-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (2S,3S)-1-cyano-2-methyl-N-(5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide-   (2S,3S)-1-cyano-2-methyl-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (2S,3S)—N-(5-(2-chlorophenyl)thiazol-2-yl)-1-cyano-2-methylpyrrolidine-3-carboxamide-   1-cyano-3-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-3-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   1-cyano-3-(methoxymethyl)-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   1,3-dicyano-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   (3S,4S)-1-cyano-4-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   (3S,4S)-1-cyano-4-methyl-N-(5-methylthiazol-2-yl)pyrrolidine-3-carboxamide-   (3S,4S)—N-(5-(2-chlorophenyl)thiazol-2-yl)-1-cyano-4-methylpyrrolidine-3-carboxamide-   (3S,4S)-1-cyano-4-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (3S,4S)-1-cyano-4-ethyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   (3S,4S)-1-cyano-4-ethyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   1-cyano-5-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-5-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   1-cyano-5-methyl-N-(5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-morpholinothiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(4-methylpiperazin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   N-(5-(2-(acetamidomethyl)piperidin-1-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(5-(methyl(phenyl)amino)thiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(indolin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(isoindolin-2-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(3,4-dihydroisoquinolin-2(1H)-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-((R)-2-(methoxymethyl)pyrrolidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-((S)-2-(methoxymethyl)pyrrolidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(5-oxo-1,4-diazepan-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (R)-1-cyano-N-(5-morpholinothiazol-2-yl)pyrrolidine-3-carboxamide-   (R)-1-cyano-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (3S,4S)-1-cyano-4-methyl-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-5-methyl-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(pyrrolidin-1-yl)pyridine-3-carboxamide-   (S)-1-cyano-N-(4-(pyrrolidin-1-yl)pyridine-3-carboxamide-   (S)-1-cyano-N-(5-(pyrrolidin-1-yl)pyrazin-2-yl)pyrrolidine-3-carboxamide-   N-(5-(2-aminophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   N-(5-(3-aminophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   N-(5-(4-aminophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(5-(pyridin-3-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (E)-1-cyano-N-(5-(2-cyclopropylvinyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   N-(5-(4-acetamidophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   N-(5-(2-acetamidophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   1-cyano-N-(5-(3-(methylsulfonamido)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(3-cyanophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-cyanophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(3,5-dimethylisoxazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(4-methoxyphenyl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-phenylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(1-methyl-1H-pyrazol-5-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(3,5-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(5-methylisoxazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(6-cyclopropylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(3,6-dimethoxypyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(3,6-dimethoxypyridazin-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (2S,3S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)benzo[d]thiazol-2-yl)-2-methylpyrrolidine-3-carboxamide-   1-cyano-N-(5-(p-tolyl)pyridin-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(m-tolyl)pyridin-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(o-tolyl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)-5-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)-7-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(7-methyl-6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(morpholinomethyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   1-cyano-N-(5-(pyrrolidin-1-ylmethyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (3S)-1-cyano-N-(5-((2,6-dimethylmorpholino)methyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (2S,3S)-1-cyano-N-(5-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)-2-methylpyrrolidine-3-carboxamide-   (S)—N-(1-benzyl-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-phenethyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-isobutyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (2S,3S)—N-(1-benzyl-1H-imidazol-4-yl)-1-cyano-2-methylpyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(3-fluorophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(2-fluorophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-(methylcarbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(3-(methylcarbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(2-(methylcarbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-((2-methoxyethyl)carbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(2-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-cyclohexyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (3S)-1-cyano-N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(2,3-dihydro-1H-inden-2-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-((S)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-((R)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(pyridin-4-ylmethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (2S,3S)-1-cyano-2-methyl-N-(1-((S)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (3S,4S)-1-cyano-4-methyl-N-(1-((S)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-methylpyridin-2-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (R)-1-cyano-N-(1-(2-methylpyrimidin-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-cyanophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)—N-(1-benzyl-2-methyl-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(3-cyanophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(pyridin-3-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(pyridin-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (3S)—N-(1-(1-benzoylpiperidin-3-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (3S)—N-(1-(1-benzoylpyrrolidin-3-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (3S)—N-(1-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (3S)-1-cyano-N-(1-(1-methylpiperidin-3-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (3S)-1-cyano-N-(1-(1-methylpyrrolidin-3-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-isobutyryl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-benzoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(2-methoxybenzoyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-picolinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(1-methyl-1H-pyrazole-3-carbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(1-methyl-2-oxo-1,2-dihydropyridine-3-carbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-nicotinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(dimethylglycyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   methyl    (S)-2-(1-cyanopyrrolidine-3-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5    (4H)-carboxylate-   2-methoxyethyl    (S)-2-(1-cyanopyrrolidine-3-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5    (4H)-carboxylate-   (S)-1-cyano-N-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(isopropylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(phenylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-ethynylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(3-ethynylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (3S)-1-cyano-N-(5-(N-(1-phenylethyl)sulfamoyl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (3S)-1-cyano-N-(5-(N-methyl-N-(1-phenylethyl)sulfamoyl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (3S,4S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-4-(trifluoromethyl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(N,N-dimethylsulfamoyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(pyridazin-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-cyano-3-fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-(1H-indazol-7-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(5-(3-(1H-imidazol-1-yl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-(methylsulfonamido)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-(3-(1H-pyrazol-1-yl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-cyano-3-(trifluoromethoxy)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-cyano-3-methoxyphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-sulfamoylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-(1H-indazol-6-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(5-(1H-indazol-5-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-6-(2-(1-cyanopyrrolidine-3-carboxamido)thiazol-5-yl)-N-methylpicolinamide-   (S)-6-(2-(1-cyanopyrrolidine-3-carboxamido)thiazol-5-yl)-N-ethylpicolinamide-   (S)-1-cyano-N-(5-(1-methyl-1H-indazol-5-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(1-(2-methoxyethyl)-1H-indazol-5-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(2-oxoindolin-7-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(3-methyl-1H-indazol-5-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-(1H-indazol-4-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(4-fluoro-3-(methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-(3-carbamoylphenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(3-(methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(3-(ethylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(3-(dimethylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-(3-carbamoyl-4-fluorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(5-(3-carbamoyl-4-chlorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(5-(4-chloro-3-(methylcarbamoyl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(5-(4-chloro-3-(prop-2-yn-1-ylcarbamoyl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(isopropylsulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(5-benzyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-cyano-3-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(2-cyano-5-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-cyano-3-(3-morpholinopropoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(2-cyano-5-(3-morpholinopropoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-cyano-3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(2-cyano-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-cyano-3-(oxetan-3-yloxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(2-cyano-5-(oxetan-3-yloxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-(imidazo[1,2-a]pyrimidin-5-yl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-(imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-(imidazo[1,2-a]pyrazin-6-yl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-(imidazo[1,2-a]pyrimidin-6-yl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1,7-naphthyridin-6-yl)pyrrolidine-3-carboxamide-   (S)—N-(6-(3-chlorophenyl)pyrimidin-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(2′-amino-[4,4′-bipyridin]-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(2′-(methyl    amino)-[4,4′-bipyridin]-2-yl)pyrrolidine-3-carboxamide-   (S)-3-(1-cyanopyrrolidine-3-carboxamido)—N-methylisoquinoline-6-carboxamide-   (S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide-   (S)—N-(4-(1H-indazol-4-yl)pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-ethynylisoquinolin-3-yl)pyrrolidine-3-carboxamide-   (2S,3S)-1-cyano-N-(6-ethynylisoquinolin-3-yl)-2-methylpyrrolidine-3-carboxamide-   (S)-3-(1-cyanopyrrolidine-3-carboxamido)isoquinoline-6-carboxamide-   (2S,3S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-cyano-2-methylpyrrolidine-3-carboxamide-   (S)-1-cyano-N-(pyrazolo[1,5-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-phenylpyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(pyridin-3-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(pyridin-3-yl)thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-methyl-5-(m-tolyl)-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(quinolin-3-yl)pyrrolidine-3-carboxamide-   (S)—N-(4-(tert-butyl)pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(pyridin-4-yl)pyrimidin-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-phenylpyridazin-3-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(oxazol-5-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(isopropylsulfonyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   3-cyano-N-(5-phenylthiazol-2-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide-   2-cyano-N-(5-phenylthiazol-2-yl)-2-azabicyclo[3.1.0]hexane-4-carboxamide-   (3S,4S)-1-cyano-N-(5-phenylthiazol-2-yl)-4-(trifluoromethyl)pyrrolidine-3-carboxamide-   (3S,4R)-1-cyano-N-(5-phenylthiazol-2-yl)-4-(pyridin-3-yl)pyrrolidine-3-carboxamide-   (3S,4R)-1-cyano-N-(5-phenylthiazol-2-yl)-4-(pyrimidin-5-yl)pyrrolidine-3-carboxamide-   1-cyano-3-methoxy-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)thiazolo[4,5-b]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(5-(3,5-dimethylisoxazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(2,6-dimethylphenyl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(1,3-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(5-(trifluoromethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-(3-(5-methylisoxazol-4-yl)phenyl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)—N-(4-(1H-pyrazol-4-yl)pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(1-(4-(1H-pyrazol-4-yl)phenyl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(4-(5-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)thiazolo[4,5-c]pyridin-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(2′-(5-methylisoxazol-4-yl)-[4,4′-bipyridin]-2-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(1,3-dimethyl-1H-indazol-5-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(3-methyl-1H-indazol-6-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)—N-(1-(1H-indazol-5-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)—N-(1-(1H-indazol-6-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)—N-(1-(1H-indazol-4-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-cyano-3-cyclopropylphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(quinolin-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-methyl-N-(4-(4-(methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-2-carboxamide-   (S)-1-cyano-N-(1-(4-cyano-3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-cyano-3-methylphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-cyano-3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide-   (S)-1-cyano-N-(1-(4-cyano-3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

It should be noted that each of the chemical compounds listed aboverepresents a particular and independent aspect of the invention.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula (I) or apharmaceutically acceptable salt thereof comprising the steps ofreacting an acid of formula (V) with a compound R₁—NH₂ to form an amide:

Where R₂-R₈ are as defined elsewhere and Pg is an amine protectinggroup. The protecting group may be but is not limited to BOC. It isclear to a person skill in the art to combine or adjust such aprotecting chemical group. After coupling of R₁—NH₂ to form an amide,the protecting group may be removed to leave the free amine according toformula (VI) which can then be treated with cyanogen bromide to formcpds according to formula (I).

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula (I) or apharmaceutically acceptable salt thereof comprising the steps ofreacting an amine of formula (VI) with cyanogen bromide to form N—CNcompounds:

According to a further aspect of the invention there is provided apharmaceutical composition comprising a compound of formula (I).

Pharmaceutical compositions of this invention comprise any of thecompounds of formula (I) of the invention combined with anypharmaceutically acceptable carrier, adjuvant or vehicle. Examples ofpharmaceutically acceptable carriers, are known to those skilled in theart and include but are not limited to preserving agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavouring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispersing agents, depending on the nature of the mode of administrationand dosage forms. The compositions may be in the form of, for example,tablets, capsules, powders, granules, elixirs, lozenges, suppositories,syrups and liquid preparations including suspensions and solutions. Theterm “pharmaceutical composition” in the context of this invention meansa composition comprising an active agent and comprising additionally oneor more pharmaceutically acceptable carriers. The composition mayfurther contain ingredients selected from, for example, diluents,adjuvants, excipients, vehicles, preserving agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavouring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispersing agents, depending on the nature of the mode of administrationand dosage forms.

According to a further aspect of the invention there is provided acompound of formula (I) or pharmaceutical composition thereof for use intherapy. In particular compounds of the invention according to formula(I) have use in the treatment of cancer and more particularly in thetreatment of cancers linked to DUB activity Compounds of the inventionmay be useful against any DUB enzyme, including by not limited to UCHL1,USP6 or USP30.

The compounds of formula (I) as described herein may be used in themanufacture of a medicament for the treatment of a cancer linked to DUBactivity.

UCHL1 is overexpressed in many turnout types. In a further aspect of theinvention there is provided a method of treatment or prevention of acancer linked to UCHL1 activity, the method comprising administering apharmaceutically effective amount of a compound of formula (I) of apharmaceutical composition thereof to an individual suffering from acancer linked to UCHL1 activity.

The compounds or compositions according to formula (I) may be used totreat cancer. References to “cancer” or “tumour” include but are notlimited to breast, ovarian, prostate, lung, kidney, gastric, colon,testicular, head and neck, pancreas, brain, melanoma, bone or othercancers of tissue organs and cancers of the blood cells such aslymphomas and leukaemias. Particular cancers include breast, lymphoma,multiple myeloma, colorectal cancer, osteosarcoma, pancreatic and nonsmall cell lung carcinoma.

The compounds or compositions according to formula (I) may be used totreat additional disease linked to UCHL1 activity. For example a diseaselinked to UCHL1 activity may be selected from neurodegenerativedisorders (such as Alzheimer's disease, Parkinson's disease), COPD,inflammation, viral infections, including MERS or SARS, bacterialinfections, including tuberculosis or metabolic disorders.

The compounds of formula (I) or pharmaceutical compositions thereof asdescribed herein may be combined with one or more additional agents. Thecompounds may be combined with an additional anti-tumour therapeuticagent, for example chemotherapeutic drugs or inhibitors of otherregulatory proteins. In one embodiment the additional anti-tumourtherapeutic agent is selected from a PARP (poly ADP ribose polymerase)inhibitor, a BRCA2 inhibitor and an ATM inhibitor. In anotherembodiments the PARP inhibitor is an inhibitory RNA (RNAi) molecule(PARPi). In a further embodiment PARP inhibitors may be selected fromone or more of Iniparib (BSI 201), Olaparib (AZD-2281), Rucaparib(AG014699, PF-01367338) and Veliparib (ABT-888), MK-4827, CEP-9722, E716(GPT-221016), LT-673, MP-124, NMS-P118. In a further embodiment theadditional anti-tumour agent is a chemotherapeutic agent.Chemotherapeutic agents may be selected from olaparib, mitomycin C,cisplatin, carboplatin, oxaliplatin, ionizing radiation (IR),camptothecin, irinotecan, topotecan, temozolomide, taxanes,5-fluoropyrimidines, gemcitabine, and doxorubicin.

The pharmaceutical compositions of the invention may be administered inany effective manner suitable for targeting cancer cells, for exampleorally in any orally acceptable dosage form including, but not limitedto tablets, dragees, powders, elixirs, syrups, liquid preparationsincluding suspensions, sprays, inhalants, tablets, lozenges, emulsions,solutions, cachets, granules and capsules. Such dosage forms areprepared according to techniques known in the art of pharmaceuticalformulation. When in the form of sprays or inhalants the pharmaceuticalcompositions may be administered nasally. Suitable formulations for thispurpose are known to those skilled in the art.

The pharmaceutical compositions of the invention may be administered byinjection and may be in the form of a sterile liquid preparation forinjection, including liposome preparations.

The pharmaceutical compositions of the invention may also be in the formof suppositories for rectal administration. These are formulated so thatthe pharmaceutical composition is solid at room temperature and liquidat body temperature to allow release of the active compound.

The dosages may be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the compoundbeing employed. Determination of the proper dosage for a particularsituation is within the remit of the person skilled in the skill of theart.

Generally, treatment is initiated with smaller dosages which are lessthan the optimal dose of the compound. Thereafter the dosage isincreased by small increments until the optimum effect under thecircumstances is reached.

The magnitude of an effective dose of a compound will, of course, varywith the nature of the severity of the condition to be treated and withthe particular compound and its route of administration. The selectionof appropriate dosages is within the ability of one of ordinary skill inthis art, without undue burden. The daily dose range is about 10 μg toabout 100 mg per kg body weight of a human and non-human animal and ingeneral may be around 10 μg to 30 mg per kg body weight per dose. Theabove dose may be given from one to three times per day.

Synthetic Methodologies

Compounds of the invention may be prepared via a variety of syntheticroutes. Exemplary routes to certain compounds of the invention are shownbelow. Representative compounds of the present invention can besynthesized in accordance with the general synthetic methods describedbelow and are illustrated more particularly in the schemes that follow.Since the schemes are an illustration, the invention should not beconstrued as being limited by the chemical reactions and conditionsexpressed. The preparation of the various starting materials used in theschemes is well within the skill of persons versed in the art. Thoseskilled in the art appreciate that, where appropriate, the individualtransformations within a scheme can be completed in a different order.The following schemes describe general synthetic methods wherebyintermediate and target compounds of the present invention may beprepared. Additional representative compounds and stereoisomers, racemicmixtures, diastereomers and enantiomers thereof can be synthesized usingthe intermediates prepared in accordance to the general schemes andother materials, compounds and reagents known to those skilled in theart. All such compounds, stereoisomers, racemic mixtures, diastereomersand enantiomers thereof are intended to be encompassed within the scopeof the present invention.

All the compounds were characterised by liquid chromatography-massspectroscopy (LCMS) and ¹H NMR.

Abbreviations

-   aq Aqueous-   Ar Aryl-   BOC Tert-butoxycarbonyl-   br Broad (NMR signal)-   d Doublet (NMR signal)-   dba dibenzylideneacetone-   DCE 1,2-Dichloroethane-   DCM Dichloromethane-   DIAD Diisopropyl azodicarboxylate-   DIPEA Diisopropylethylamine-   DMA Dimethylacetamide-   DMAP Dimethylaminopyridine-   DMF Dimethylformamide-   DMSO Dimethylsulphoxide-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-   ES Electrospray-   EtOAc Ethyl acetate-   EtOH Ethanol-   FA Formic Acid-   Fmoc Fluorenylmethyloxycarbonyl-   h Hour(s)-   HATU    (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate)-   HBTU    O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate-   HPLC High performance liquid chromatography-   HOAt 1-Hydroxy-7-azabenzotriazole-   IPA Isopropyl alcohol-   LDA Lithium diisopropylamide-   LiHMDS Lithium Hexamethyldisilazide-   m Multiplet (NMR signal)-   MeCN Acetonitrile-   MeOH Methanol-   n-BuLi n-Butyllithium-   rt Room temperature-   s Singlet (NMR signal)-   t Triplet (NMR signal)-   T3P    2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide-   TBAI Tetrabutylammonium Iodide-   TEA Triethylamine-   TFA Trifluoroacetic acid-   TFAA Trifluoroacetic anhydride-   THF Tetrahydrofuran-   X-phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Analytical Methods:

Method A Column BEH C18, 50 × 2.1 mm, 1.7 μm or equivalent Mobile (A) 5mM Ammonium Acetate + 0.1% Formic Acid in Water Phase (B) 0.1% FormicAcid in Acetonitrile Flow Rate 0.55 mL/min Time % B Gradient 0.01 5 0.405 0.80 35 1.20 55 2.50 100 3.30 100 3.31 5 4.00 5

Method B Column BEH C18, 50 × 2.1 mm, 1.7 μm or equivalent Mobile (A) 5mM Ammonium Acetate + 0.1% Formic Acid in Water Phase (B) 0.1% FormicAcid in Acetonitrile Flow Rate 0.45 mL/min Time % B Gradient 0.01 2 0.502 5.00 90 6.00 95 7.00 95 7.01 2 8.00 2

Method C Column X-bridge C18 50 × 4.6 mm, 3.5 μm or equivalent MobilePhase (A) 0.1% Ammonia in Water (B) 0.1% Ammonia in Acetonitrile FlowRate 1.0 mL/min Time % B Gradient 0.01 5 5.00 90 5.80 95 7.20 95 7.21 510.00 5

Synthetic Schemes:

Intermediate 1((2S,3S)-1-[(tert-butoxy)carbonyl]-2-methylpyrrolidine-3-carboxylicacid)

Step a.

To a solution of methyl acetoacetate (1.72 mol) and 1,2-dibromoethane(1.90 mol) in acetone (2000 ml) was added K₂CO₃ (2.59 mol) at rt. Thereaction mixture was heated at 70° C. for 24 h. The resulting reactionmixture was allowed to cool to rt and filtered through celite hyflow.The celite cake was washed with acetone (2×100 ml). The filtrate wasconcentrated under reduced pressure and the resulting residue waspurified by column chromatography (4% EtOAc in hexane) yielding methyl1-acetylcyclopropane-1-carboxylate (0.70 mol). MS: ES+ 143.14.

Step b.

A solution of methyl 1-acetylcyclopropane-1-carboxylate (0.70 mol) and(S)-1-phenylethan-1-amine (0.84 mol) in toluene (1000 ml) was charged ina dean stark glass assembly. The reaction mixture was heated at atemperature (130-140° C.) to remove the water by azeotropicdistillation. The process was continued for 22 h. The reaction mixturewas allowed to cool to rt and concentrated under reduced pressure. Theresulting residue was purified by column chromatography (2% EtOAc inhexane) yielding methyl(S)-2-methyl-1-(1-phenylethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate(0.37 mol). MS: ES+ 246.33; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.36-7.39(m, 2H), 7.26-7.29 (m, 3H), 4.95 (q, J=7.01 Hz, 1H), 3.50 (s, 3H),3.41-3.49 (m, 1H), 3.03-3.10 (m, 1H), 2.55-2.57 (m, 2H), 2.25 (s, 3H),1.48 (d, J=7.01 Hz, 3H).

Step c.

To a solution of(S)-2-methyl-1-(1-phenylethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (375mmol) in MeCN (1000 ml) was added acetic acid (300 ml) at 0° C. Sodiumtriacetoxyborohydride (751 mmol) was added at 0° C. in equal portions.The reaction mixture was stirred at 0° C. for 3 h and the resultingreaction mixture was distilled under reduced pressure to remove majorityof MeCN. The resulting mixture was poured into ice water (500 ml) andwas neutralized by solid Na₂CO₃. The resulting mixture was extractedwith EtOAc (3×200 ml). The combined organic phase was collected, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography (2 to 10% EtOAcin hexane) yielding (210 mmol) of the title compound as a mixture ofdiastereomers. The diastereomeric mixture was further crystallized fromhexane (350 ml) at −70° C. yielding methyl(2S,3S)-2-methyl-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylate (137mmol). MS: ES+ 248.15; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.28-7.36 (m,4H), 7.19-7.24 (m, 1H), 3.59 (s, 3H), 3.55-3.58 (m, 1H), 3.31-3.39 (m,1H), 3.03-3.10 (m, 1H), 2.56-2.62 (m, 1H), 2.40-2.46 (m, 1H), 1.93-2.04(m, 1H), 1.76-1.84 (m, 1H), 1.25 (d, J=6.71 Hz, 3H), 0.71 (d, J=6.40 Hz,3H).

Step d.

A solution of methyl(2S,3S)-2-methyl-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylate (137mmol) in MeOH (700 ml) was charged in an autoclave vessel at rt undernitrogen atmosphere. 10% Pd/C (0.3% w/w) was added to the reactionmixture at rt under nitrogen atmosphere. The resulting reaction mixturewas stirred in the autoclave at rt under 425 psi H₂ pressure for 16 h.The resulting reaction mixture was carefully filtered through celitehyflow and concentrated under reduced pressure to yield methyl(2S,3S)-2-methylpyrrolidine-3-carboxylate (quantitative). The materialwas immediately used for the next step. MS: ES+ 144.05; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.59 (s, 3H), 3.18-3.25 (m, 1H), 2.96-3.02 (m, 1H),2.82-2.88 (m, 1H), 2.61-2.66 (m, 1H), 1.80-1.97 (m, 2H), 0.94 (d,J=6.714 Hz, 3H).

Step e.

To stirred a solution of methyl(2S,3S)-2-methylpyrrolidine-3-carboxylate (139 mmol) in THF (200 ml)were added DMAP (8.1 mmol) and BOC anhydride (751 mmol) at 0° C. Thereaction mixture stirred at 0° C. for 16 h. The resulting reactionmixture was poured into water (100 ml) and extracted with DCM (2×200ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography (10% EtOAc in hexane) yielding1-(tert-butyl) 3-methyl (2S,3S)-2-methylpyrrolidine-1,3-dicarboxylate(111 mmol). MS: ES+ 188 (M-56) 144 (M-100); ¹H NMR (400 MHz, DMSO-d₆) δppm 3.98-4.03 (m, 1H), 3.64 (s, 3 H), 3.30-3.41 (m, 1H), 3.12-3.29 (m,2H), 2.06-2.14 (m, 1H), 1.91-1.99 (m, 1H), 1.40 (s, 9H), 0.95 (d, J=6.40Hz, 3H).

Step f.

A solution of 1-(tert-butyl) 3-methyl(2S,3S)-2-methylpyrrolidine-1,3-dicarboxylate (111 mmol) in mixture ofMeOH:water (1:1, 400 ml) was stirred at 0° C. for 10 min. Solid LiOH(166 mmol) was added portion wise to the reaction mixture at 0° C. Thereaction mixture was stirred at 20° C. for 6 h. The resulting reactionmixture was extracted with EtOAc (2×100 ml). The aqueous layer wascooled to 0° C. and was neutralised by slow addition of 1N HCl. Theresulting mixture was extracted with EtOAc (3×200 ml). The combinedorganic phase was dried over Na₂SO₄, filtered and concentrated underreduced pressure yielding title compound (87.33 mmol). MS: ES− 228; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.43 (br s, 1H), 3.97-4.02 (m, 1H),3.30-3.35 (m, 1H) 3.06-3.18 (m, 2H), 2.01-2.10 (m, 1H), 1.85-1.93 (m,1H), 1.40 (s, 9H), 1.00 (d, J=5.79 Hz, 3H).

Intermediate 2(1-[(tert-butoxy)carbonyl]-(±)-trans-4-methylpyrrolidine-3-carboxylicacid)

Step a.

A solution of ethyl crotonate (17.5 mmol) andN-benzyl-O-ethyl-N-((trimethylsilyl)methyl) hydroxyl amine (19.2 mmol)in toluene (40 ml) was stirred at rt for 5 min. TFA (17.5 mmol) wasadded dropwise to the reaction mixture at rt. The reaction mixture wasthen heated at 50° C. for 16 h. The resulting reaction mixture waspoured into water (100 ml) and basified with solid NaHCO₃. The resultingmixture was extracted with EtOAc (2×180 ml). The combined organic phasewas collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography (0-9% EtOAc in hexane) yieldingethyl-(±)-trans-1-benzyl-4-methylpyrrolidine-3-carboxylate (9.0 mmol).MS: ES+ 248.33; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.24-7.36 (m, 5H), 4.13(q, J=8.0, 5.2 Hz, 2H), 3.67 (d, J=13 Hz, 1H), 3.58 (d, J=13 Hz, 1H),2.77-2.91 (m, 3H), 2.47-2.59 (m, 2H), 2.21-2.26 (m, 1H), 1.27 (t, J=7.2Hz, 3H), 1.16 (d, J=6.71 Hz, 3H).

Step b.

To a solution ofethyl-(±)-trans-1-benzyl-4-methylpyrrolidine-3-carboxylate (10 mmol) inethanol (30 ml) were added polymethyl hydrosiloxane (1.0 w/w), 20%Pd(OH)₂ on carbon (0.5 w/w) and BOC anhydride (20 mmol) at 0° C. Thereaction mixture was stirred at rt for 1.5 h. The resulting reactionmixture was carefully filtered through celite hyflow and the filtratewas concentrated under reduced pressure. The resulting residue waspurified by column chromatography (0-10% EtOAc in hexane) yielding1-tert-butyl 3-ethyl (±)-4-methylpyrrolidine-1,3-dicarboxylate (8.5mmol). MS: ES+ 202.2 (M-56)

Step c.

A solution of 1-tert-butyl 3-ethyl(±)-4-methylpyrrolidine-1,3-dicarboxylate (8.5 mmol) in THF (15 ml) wasstirred at 0° C. for 5 min. A solution of NaOH (34.0 mmol) in water (15ml) was added dropwise to the reaction mixture at 0° C. The reactionmixture was stirred at rt for 16 h. The resulting reaction mixture waspoured into water (200 ml) and acidified to pH 4.0 with dilute HCl. Theobtained mixture was extracted with EtOAc (2×150 ml). The combinedorganic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding1-[(tert-butoxy)carbonyl]-(±)-trans-4-methylpyrrolidine-3-carboxylicacid (7.1 mmol). This material was used directly for the next stepwithout further purification. MS: ES− 228.28; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 12.51 (br s, 1H), 3.47-3.56 (m, 2H), 3.28-3.34 (m, 1H), 2.78-2.86(m, 1H), 2.58-2.64 (m, 1H), 2.27-2.34 (m, 1H), 1.38 (s, 9H), 1.04 (d,J=4.8 Hz, 3H).

Intermediate 3 5-(tetrahydro-2H-pyran-4-yl)thiazol-2-amine

Step a.

To a stirred solution of 2-(tetrahydro-2H-pyran-4-yl) acetaldehyde (4.7mmol), pyrrolidine (5.6 mmol) and p-toluenesulfonic acid monohydrate(0.5 mmol) in cyclohexane (20 ml) was added oven dried molecular sieves.The reaction mixture was heated at 80° C. for 3 h. The resultingreaction mixture was concentrated under reduced pressure. The obtainedresidue was re-dissolved in MeOH (3 ml) and cooled to 0° C. To thissolution were added sulphur powder (4.7 mmol) and a solution ofcyanamide (4.7 mmol) in MeOH (0.5 ml) at 0° C. The reaction mixture wasstirred at rt for 16 h. The resulting reaction mixture was concentratedunder reduce pressure, poured into water (50 ml) and extracted withEtOAc (3×50 ml). The combined organic phase was collected, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography (2-3% MeOH in DCM)yielding 5-(tetrahydro-2H-pyran-4-yl)thiazol-2-amine (1.6 mmol). MS: ES+185.14

Intermediate 4 1-methyl-5-phenyl-1H-pyrazol-3-amine

Step a.

A solution of cinnamonitrile (7.7 mmol) in MeOH (10 ml) was stirred at0° C. for 5 min. Bromine (15.5 mmol) was added to the reaction mixtureat 0° C. The reaction mixture was stirred at rt for 16 h. The resultingreaction mixture was poured into water (50 ml) and basified with solidNaHCO₃. The resulting mixture was extracted with EtOAc (3×50 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (0-4% EtOAc in hexane) yielding2,3-dibromo-3-phenylpropanenitrile (1.66 mmol). This material was usedimmediately for the next step without further purification.

Step b.

To a solution of 2,3-dibromo-3-phenylpropanenitrile (1.6 mmol) in MeOH(10 ml) was added methylhydrazine (1.6 mmol) at rt. The reaction mixturewas heated at 75° C. for 16 h. The resulting reaction mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (2-3% MeOH in DCM) yielding1-methyl-5-phenyl-1H-pyrazol-3-amine (quantitative). This material wasused directly for the next step without further purification. MS: ES+174.24

Intermediate 5 5-(4-methoxypiperidin-1-yl)pyridin-2-amine

Step a.

A solution of 5-bromo-2-nitro-pyridine (2.0 mmol) and4-methoxypiperidine HCl (4.0 mmol) in DMSO (10 ml) was stirred at rt for5 min. K₂CO₃ (4.0 mmol) and TBAI (0.2 mmol) were then added to thereaction mixture at rt. The reaction mixture was stirred at 80° C. for15 h. The resulting reaction mixture was poured into water (200 ml) andextracted with EtOAc (2×150 ml). The combined organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography(15% EtOAc in hexane) yielding5-(4-methoxypiperidin-1-yl)-2-nitropyridine (1.6 mmol). MS: ES+ 238.35;¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (d, J=3.05 Hz, 1H), 8.14 (d, J=9.16Hz, 1H), 7.49 (dd, J=9.16, 3.05 Hz, 1H), 3.75-3.84 (m, 2H), 3.46-3.48(m, 1H), 3.30-3.35 (m, 2H), 3.28 (s, 3H), 1.90-1.95 (m, 2H), 1.48-1.53(m, 2H).

Step b.

To a solution of 5-(4-methoxypiperidin-1-yl)-2-nitropyridine (1.6 mmol)in MeOH (20 ml) was added 10% Pd/C (0.25% w/w) at rt. The reactionmixture was purged with H₂ gas at rt for 1 h. The resulting reactionmixture was carefully filtered through celite hyflow and concentratedunder reduced pressure to yield5-(4-methoxypiperidin-1-yl)pyridin-2-amine (1.55 mmol). MS: ES+ 208.08;¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.61 (d, J=3.05 Hz, 1H), 7.16 (dd,J=8.85, 2.75 Hz, 1H), 6.38 (d, J=8.85 Hz, 1H), 5.40 (br s, 2H),3.22-3.31 (m, 4H), 3.15-3.22 (m, 2H), 261-271 (m, 2H), 1.88-1.97 (m,2H), 1.46-1.58 (m, 2H).

Intermediate 6 5-cyclohexylpyridin-2-amine

Step a.

Pd(dppf)Cl₂.CH₂Cl₂ (0.06 mmol) was added to a solution of2-amino-5-bromopyridine (2.8 mmol) in 1,4-dioxane (5 ml) at 0° C. Theresulting reaction mixture was allowed to stir at 0° C. Meanwhile afresh Grignard solution was prepared by adding cyclohexylmagnesiumbromide (1M in THF) (11.5 mmol) to ZnCl₂ (0.7M in THF) (5.8 mmol) at 0°C. The Grignard solution was diluted by dropwise addition of 1,4-dioxane(10 ml) at 0° C. The freshly prepared Grignard solution was addeddropwise to the reaction mixture maintaining the temperature at 0° C.The resulting reaction mixture was then allowed to reach at rt and thenrefluxed for 20 h. The resulting reaction mixture was cooled and thenpoured into saturated NaHCO₃ solution (25 ml) and extracted with EtOAc(3×50 ml). The combined organic phase was dried over Na₂SO₄, filteredand concentrated under reduced pressure. The resulting residue waspurified by flash chromatography (40-50% EtOAc in hexane) yielding5-cyclohexylpyridin-2-amine (2.3 mmol). MS: ES+ 177.19.

Intermediates 7 and 8 6-(1H-1,2,3-triazol-1-yl)benzo[d]thiazol-2-amineand 6-(2H-1,2,3-triazol-2-yl)benzo[d]thiazol-2-amine

Step a.

A solution of 1,2,3-triazole (14.17 mmol) and Cs₂CO₃ (35.5 mmol) in DMF(20 ml) was stirred at rt for 30 min. 1-Fluoro-4-nitrobenzene (14.17mmol) was added to the reaction mixture at rt and then stirred at 70° C.for 3 h. The resulting reaction mixture was poured into a chilled brinesolution (50 ml). The obtained white precipitates were collected byfiltration under reduced pressure and washed with chilled water (2×10ml). The obtained solid was a mixture of regio-isomers which werefurther separated by column chromatography (0-9% EtOAc in hexane)yielding 1-(4-nitrophenyl)-1H-1,2,3-triazole (4.3 mmol) MS: ES+ 191.34;¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.08 (d, J=1.22 Hz, 1H), 8.45-8.49 (m,2H), 8.24-8.30 (m, 2H), 8.09 (d, J=1.22 Hz, 1H) and2-(4-nitrophenyl)-2H-1,2,3-triazole (5.8 mmol) MS: ES+ 191.3; H NMR (400MHz, DMSO-d₆) δ ppm 8.43-8.46 (m, 2H), 8.27-8.30 (m, 4H).

Step b.

To a solution of 1-(4-nitrophenyl)-1H-1,2,3-triazole (5.78 mmol) inethanol (8 ml) and water (4 ml) was added Fe power (34.73 mmol) andacetic acid (34.74 mmol) at rt. The reaction mixture was stirred at 80°C. for 1 h. The resulting reaction mixture was allowed to cool to rt andpoured into a mixture of DCM (20 ml) and water (10 ml). The obtainedemulsion was filtered through celite hyflow. Organic layer was separatedfrom the obtained filtrate and the aqueous layer was back extracted withDCM (10 ml). The combined organic phase was collected, dried overNa₂SO₄, filtered and concentrated under reduced pressure yielding4-(1H-1,2,3-triazol-1-yl)aniline (5.6 mmol). The material was useddirectly for the next step without further purification. MS: ES+ 161.102-(4-Nitrophenyl)-2H-1,2,3-triazole was processed in a similar manner toafford 4-(2H-1,2,3-triazol-2-yl)aniline. MS: ES+ 161.10

Step c.

To a solution of 4-(1H-1,2,3-triazol-1-yl)aniline (3.43 mmol) in aceticacid (5 ml) was added ammonium thiocyanate (8.59 mmol) at rt and thereaction mixture was then cooled to 10° C. Bromine (3.43 mmol) in aceticacid (2 ml) was added dropwise to the above reaction mixture at 10° C. Athick mass was observed during addition of bromine. The reaction mixturewas then stirred well at rt for 3 h. The resulting reaction mixture waspoured into chilled water (30 ml) and neutralized using ammoniumhydroxide. Obtained yellow precipitates were collected by filtrationunder reduced pressure, washed with chilled water (2×10 ml), MeOH (2×5ml) and dried to yield 6-(1H-1,2,3-triazol-1-yl)benzo[d]thiazol-2-amine(2.85 mmol). MS: ES+ 218.13; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.73 (d,J=0.92 Hz, 1H), 8.23 (d, J=2.14 Hz, 1H), 7.95 (d, J=0.92 Hz, 1H), 7.75(s, 2H), 7.71 (dd, J=8.55, 2.44 Hz, 1H), 7.48 (d, J=8.55 Hz, 1H).4-(2H-1,2,3-triazol-2-yl)aniline was processed in a similar manner toafford 6-(2H-1,2,3-triazol-2-yl)benzo[d]thiazol-2-amine. MS: ES+ 218.13;¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.35 (s, 1H), 8.08-8.11 (m, 2H), 7.88(d, J=9.16 Hz, 1H), 7.69 (br s, 2H), 7.45 (d, J=8.85 Hz, 1H).

Intermediate 9 4-(2-aminothiazol-5-yl)-N-methylbenzamide

Step a.

A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (7.9 mmol), methyl4-bromobenzoate (11.9 mmol) and KOAc (23.97 mmol) in DMA (50 ml) wasprepared in a glass tube. A stream of nitrogen gas was purged throughthe reaction mixture at rt for 30 min. Pd(PPh₃)₄ (0.79 mol) was added tothe reaction mixture and the glass tube was tightly sealed. The sealedtube was heated at 140° C. (external temperature) for 16 h. Theresulting reaction mixture was poured into water (100 ml) and extractedwith EtOAc (2×50 ml). The combined organic phase was collected, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography (25% EtOAc inhexane) yielding methyl4-(2-((2,4-dimethoxybenzyl)-amino)thiazol-5-yl)benzoate (3.9 mmol). MS:ES+ 385.68

Step b.

To a solution of methyl4-(2-((2,4-dimethoxybenzyl)amino)thiazol-5-yl)benzoate (1.8 mmol) andDIPEA (0.9 mmol) in toluene (15 ml) was added trimethylaluminium (2 M intoluene) (9.1 mmol) at 0° C. The reaction mixture was stirred at 0° C.for 15 min. Methylamine (2.18 mmol) was added to the reaction mixtureand then heated at 100° C. for 16 h. The resulting reaction mixture wasconcentrated under reduced pressure and the obtained residue was pouredinto saturated NaHCO₃ solution (30 ml). The resulting mixture wasextracted with EtOAc (2×20 ml). The combined organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure yielding4-(2-((2,4-dimethoxybenzyl)amino)thiazol-5-yl)-N-methylbenzamide (0.86mmol). MS: ES+ 384.38

Step c.

To a solution of4-(2-((2,4-dimethoxybenzyl)amino)thiazol-5-yl)-N-methylbenzamide (0.80mmol) in DCM (5 ml) was added TFA (3 ml) at 0° C. The reaction mixturewas stirred at rt for 48 h. The resulting reaction mixture was pouredinto water (10 ml) and extracted with EtOAc (2×10 ml). The combinedorganic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding4-(2-aminothiazol-5-yl)-N-methylbenzamide TFA salt (0.63 mmol). Thismaterial was directly used for the next step without furtherpurification. MS: ES+ 234.35

Intermediate 10 5-(2-chlorophenyl) thiazol-2-amine

Synthesised using a procedure similar to that described for Intermediate9 using 1-bromo-2-chlorobenzene (CAS Number 694-80-4) in step a. MS: ES+211.13; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.55 (dd, J=7.6 Hz, 1.6 Hz, 1H),7.50 (dd, J=6.0 Hz, 1.2 Hz, 1H), 7.36 (s, 1H), 7.33 (dd, J=6.0 Hz, 1.2Hz, 1H), 7.25-7.29 (m, 1H), 7.21 (br s, 2H).

Intermediate 111-(tert-butoxycarbonyl)-3-(methoxymethyl)pyrrolidine-3-carboxylic acid

Step a.

A solution of 1-(tert-butyl) 3-ethyl pyrrolidine-1,3-dicarboxylate (2.0mmol) in THF (5 ml) was cooled to −78° C. Freshly prepared LDA (2.2mmol) was added dropwise to the reaction mixture at −78° C. The reactionmixture was stirred at −78° C. for 45 min. Bromomethyl methyl ether (2.2mmol) was added dropwise to the reaction mixture at −78° C. The reactionmixture was stirred at rt for 16 h. The resulting reaction mixture waspoured into saturated NH₄Cl solution (10 ml) and extracted with EtOAc(3×20 ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure yielding 1-(tert-butyl)3-ethyl 3-(methoxymethyl)pyrrolidine-1,3-dicarboxylate (quantitative).This material was directly used for the next step without furtherpurification. MS: ES+ 288.70

Step b.

To a solution of 1-(tert-butyl) 3-ethyl3-(methoxymethyl)pyrrolidine-1,3-dicarboxylate (2.1 mmol) in THF:water(3:1, 10 ml) was added LiOH (8.3 mmol) at rt. The reaction mixture wasstirred at rt for 16 h. The resulting reaction mixture was diluted withwater (10 ml) and adjusted to pH 3 using saturated aqueous solution ofcitric acid. The resulting mixture was extracted with DCM (3×20 ml). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure yielding1-(tert-butoxycarbonyl)-3-(methoxymethyl)-pyrrolidine-3-carboxylic acid(0.96 mmol). This material was directly used for the next step withoutfurther purification. MS: ES− 257.40

Intermediate 12 1-(tert-butoxycarbonyl)-3-cyanopyrrolidine-3-carboxylicacid

Step a.

A solution of tert-butyl 3-cyanopyrrolidine-1-carboxylate (2.8 mmol) inTHF (5 ml) was cooled to −78° C. LiHMDS (1M in Hexane) (7.0 mmol) wasadded dropwise to the reaction mixture at −78° C. The reaction mixturewas stirred at −78° C. for 30 min. Ethyl chloroformate (8.4 mmol) wasadded dropwise to the reaction mixture at −78° C. The reaction mixturewas stirred at rt for 1 h. The resulting reaction mixture was re-cooledto −78° C. and quenched with saturated NH₄Cl solution (10 ml). Theresulting mixture was extracted with EtOAc (3×20 ml). The combinedorganic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding 1-(tert-butyl) 3-ethyl3-cyanopyrrolidine-1,3-dicarboxylate (quantitative). This material wasdirectly used for the next step without further purification. MS: ES+269.60

Step b.

To a solution of 1-(tert-butyl) 3-ethyl3-cyanopyrrolidine-1,3-dicarboxylate (1.8 mmol) in THF:water (3:1, 13ml) was added LiOH (5.6 mmol) at rt. The reaction mixture was stirred atrt for 16 h. The resulting reaction mixture was diluted with water (10ml) and adjusted to pH 3 using saturated aqueous solution of citricacid. The resulting mixture was extracted with EtOAc (3×20 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding1-(tert-butoxycarbonyl)-3-cyanopyrrolidine-3-carboxylic acid (0.8 mmol).This material was directly used for the next step without furtherpurification. MS: ES− 239.50

Intermediate 13 tert-butyl (4-methyl-5-(morpholinomethyl)thiazol-2-yl)carbamate

Step a.

To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (10.75mmol) in THF (15 ml) were added (BOC)₂O (12.90 mmol), DMAP (1.07 mmol)and TEA (16.13 mmol) at rt. The reaction mixture was stirred at rt for18 h. The resulting reaction mixture was diluted with EtOAc (180 ml) andwashed with 1M HCl (100 ml) and brine (100 ml). The organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure yielding ethyl2-((tert-butoxycarbonyl)amino)-4-methylthiazole-5-carboxylate (8.39mmol). This material was used directly for the next step without furtherpurification.

Step b.

To a solution of ethyl 2-((tert-butoxycarbonyl)amino)-4-methylthiazole-5-carboxylate (8.39 mmol) in THF (15 ml) wasadded LiAlH₄ (2.0M in THF) (10.06 mmol) at 0° C. The reaction mixturewas stirred at rt for 2 h. The resulting reaction mixture was pouredinto water (100 ml). The obtained mixture was filtered through celitehyflow and washed with EtOAc (50 ml). The organic layer was separatedfrom the filtrate and the aqueous layer was further extracted with EtOAc(3×150 ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure yielding tert-butyl(5-(hydroxymethyl)-4-methylthiazol-2-yl)carbamate (7.17 mmol). Thismaterial was directly used for the next step without furtherpurification. MS: ES+ 245.33

Step c.

To a solution of tert-butyl (5-(hydroxymethyl)-4-methylthiazol-2-yl)carbamate (7.17 mmol) in DCM (80 ml) was added Dess-Martin periodinane(7.05 mmol) at rt. The reaction mixture was stirred at rt for 24 h. Theresulting reaction mixture was poured into water (100 ml). The obtainedmixture was neutralized by addition of aqueous solution of saturatedNaHCO₃. The resulting mixture was extracted with DCM (2×100 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding tert-butyl(5-formyl-4-methylthiazol-2-yl) carbamate (4.00 mmol). This material wasdirectly used for the next step without further purification. MS: ES+243.48

Step d.

To a solution of tert-butyl (5-formyl-4-methylthiazol-2-yl) carbamate(4.00 mmol) in DCE (5 ml) was added morpholine (8.01 mmol) at rt. Thereaction mixture was heated at 35° C. for 3 h. NaBH(OAc)₃ (12.02 mmol)was added to the reaction mixture at 35° C. The reaction mixture wasthen heated at 60° C. for 5 h. The resulting reaction mixture wasallowed to cool to rt, poured into ice water (100 ml) and extracted withDCM (3×100 ml). The combined organic phase was collected, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by flash chromatography (5% MeOH in DCM) yieldingtert-butyl (4-methyl-5-(morpholinomethyl)thiazol-2-yl)carbamate (2.55mmol). MS: ES+ 314.43

Step e.

To a solution of tert-butyl(4-methyl-5-(morpholinomethyl)thiazol-2-yl)carbamate (2.55 mmol) in DCM(10 ml) was added TFA (25.5 mmol) at 0° C. The reaction mixture wasstirred at rt for 3 h. The resulting reaction mixture was concentratedunder reduced pressure. The obtained residue was triturated with diethylether (2×5 ml) yielding 4-methyl-5-(morpholinomethyl) thiazol-2-amineTFA salt (1.69 mmol). This material was directly used for the next stepwithout further purification. MS: ES+ 214.15

Intermediate 14 tert-butyl(S)-3-((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate

Step a.

To a solution of piperidin-4-one hydrochloride (37.31 mmol) in aceticacid (30 ml) was added 30% HBr in acetic acid (0.47 ml) and 4.8 Mbromine in acetic acid (3.0 ml) at rt. The reaction mixture was stirredat rt for 1 h. The resulting reaction mixture was concentrated underreduced pressure to give a residue which was suspended in acetone (100ml) and refluxed for 1 h. The resulting solid precipitates werecollected by filtration under reduced pressure, washed with acetone (30ml) and dried to yield 3-bromopiperidin-4-one hydrobromide (31.28 mmol).The material was used directly for the next step without furtherpurification. MS: ES+ 178.0, 180.0

Step b.

To a solution of 3-bromopiperidin-4-one hydrobromide (31.39 mmol) inethanol (100 ml) was added thiourea (32.0 mmol) and the reaction mixturewas heated at 80° C. for 16 h. The resulting reaction mixture wasallowed to cool to rt. Precipitation was observed in the reactionmixture. The obtained precipitates were collected by filtration underreduced pressure, washed with ethanol (50 ml) and dried to yield4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine hydrobromide(quantitative). The material was used directly for the next step withoutfurther purification. MS: ES+ 156.19

Step c.

To a solution of 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-aminehydrobromide (31.77 mmol) in 1,4-dioxane (47 ml) were added water (75ml), K₂CO₃ (63.5 mmol) and Fmoc-Cl (47.0 mmol) at 0° C. The reactionmixture was allowed to warm to rt and was stirred for 3 h. The resultingreaction mixture was poured into water (500 ml) and extracted with DCM(3×100 ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography (2% MeOH in DCM) yielding(9H-fluoren-9-yl)methyl-2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(11.93 mmol). MS: ES+ 378.54; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.85-7.90(m, 2H), 7.63-7.65 (m, 2H), 7.40-7.44 (m, 2H), 7.30-7.34 (m, 2H), 6.83(br s, 2H), 4.31-4.42 (m, 5H), 3.47-3.60 (m, 2H), 2.29-2.43 (m, 2H).

Step d.

To a solution of (3S)-BOC-1-pyrrolidine-3-carboxylic acid (8.37 mmol) inTHF (20 ml) was added T3P (50% in EtOAc) (25.11 mmol) at rt. Thereaction mixture was stirred for min. (9H-fluoren-9-yl)methyl2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (10.04mmol) and DIPEA (25.11 mmol) were added to the reaction mixture andstirred at rt for 3 h. The resulting reaction mixture was poured intowater (100 ml) and extracted with EtOAc (3×100 ml). The combined organicphase was collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by flashchromatography (2-3% MeOH in DCM) yielding (9H-fluoren-9-yl)methyl(S)-2-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(3.74 mmol). MS: ES+ 575.74

Step e.

To a solution of (9H-fluoren-9-yl)methyl(S)-2-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(3.7 mmol) in MeOH (10 ml) was added piperidine (14.9 mmol) at rt. Thereaction mixture was stirred at rt for 2 h. The resulting reactionmixture was concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (4% MeOH in DCM) yielding thetert-butyl(S)-3-((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.77 mmol). MS: ES+ 353.43

Intermediate 15 6-bromo-5-methylbenzo[d]thiazol-2-amine

Step a.

To a solution of 4-bromo-3-methyl-aniline (26.88 mmol) in glacial aceticacid (77 ml) was added ammonium thiocyanate (53.68 mmol) at rt. Thereaction mixture was allowed to stir until it was almost clear. Thereaction mixture was cooled to 10° C. and a solution of bromine (26.88mmol) in glacial acetic acid (2.5 ml) was added dropwise to the reactionmixture at 10° C. The resulting reaction mixture was stirred at rt for1.5 h. The resulting precipitates were collected by filtration andwashed with cold acetic acid. The obtained off-white cake was taken upin water and adjusted to pH 9 with 1M NaOH solution. The resultingsolids were collected by filtration, washed with water (100 ml) anddried under reduced pressure yielding 14.46 mmol of a mixture of 70%6-bromo-7-methyl-benzothiazol-2-ylamine. MS: ES+ 243.1 (M) 245.1 (M+2);¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.61 (br s, 2H), 7.40, (d, J=8.8 Hz,1H), 7.10 (d, J=8.8 Hz, 1H), 2.41 (s, 3H) and 30%6-bromo-5-methyl-benzothiazol-2-ylamine. MS: ES+ 243.10; ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.88 (s, 1H), 7.57, (br s, 2H), 7.31 (s, 1H), 2.34(s, 3H).

Intermediate 16 (6-bromo-5-methylimidazo[1,2-a]pyridin-2-amine)

Step a.

A solution of 5-bromo-6-methylpyridin-2-amine (26.73 mmol) in pyridine(60 ml) was added slowly to 4-toluenesulfonyl chloride (32.08 mmol) at0° C. The reaction mixture was heated at 110° C. for 3 h. The resultingreaction mixture was concentrated under reduced pressure. The obtainedresidue was poured into water (300 ml) and stirred for 1 h at rt. Theresulting solids were collected by filtration and dried to yieldN-(5-bromo-6-methylpyridin-2-yl)-4-methylbenzenesulfonamide (13.19mmol). This material was directly used for the next step without furtherpurification. MS: ES+ 341.3, 343.28; ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.14 (s, 1H), 7.82 (t, J=7.6 Hz, 3H), 7.81 (d, J=8.0, 2 H), 6.84 (d,J=8.4 Hz, 1H), 2.39 (s, 3H), 2.35 (s, 3H).

Step b.

To a solution ofN-(5-bromo-6-methylpyridin-2-yl)-4-methylbenzenesulfonamide (13.19 mmol)in DMF (36 ml) in a glass tube was added 2-bromoacetamide (15.81 mmol)and DIPEA (15.81 mmol) at rt. The reaction mixture was heated at 80° C.for 48 h. The resulting reaction mixture was allowed to cool down to rtand concentrated under reduced pressure. The obtained residue waspurified by column chromatography (2% MeOH in DCM) yielding(Z)-2-(5-bromo-6-methyl-2-(tosylimino) pyridin-1(2H)-yl) acetamide (2.26mmol). MS: ES+ 398.0, 400.5.

Step c.

To a solution of (Z)-2-(5-bromo-6-methyl-2-(tosylimino)pyridin-1(2H)-yl)acetamide (2.26 mmol) in DCM (9 ml) was added TFAA (4.5 ml) at rt. Thereaction mixture was heated at 80° C. for 30 min. The resulting reactionmixture was allowed to cool down to rt and poured into ice water (150ml). The obtained mixture was neutralized by addition of aqueoussolution of saturated NaHCO₃. The resulting mixture was extracted withDCM (3×50 ml). The combined organic phase was collected, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography (1% MeOH in DCM) yieldingN-(6-bromo-5-methylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide(1.86 mmol). MS: ES+ 322.40, 324.38; ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.57 (br s, 1H), 8.05 (s, 1H), 7.52 (d, J=9.6, 1H), 7.43 (d, J=9.6 Hz,1H), 2.75 (s, 3H).

Step d.

To a solution of N-(6-bromo-5-methylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (3.11 mmol) in a mixtureof THF:water (3:1, 13 ml) was added solid LiOH.H₂O (12.44 mmol) portionwise at rt. The reaction mixture was stirred at rt for 48 h. Theresulting reaction mixture was poured into water (100 ml) and extractedwith EtOAc (3×50 ml). The combined organic phase was collected, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography (7% MeOH in DCM)yielding 6-bromo-5-methylimidazo[1,2-a]pyridin-2-amine (2.47 mmol) MSES+ 226.0, 227.90; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.20 (d, J=9.20 Hz,1H), 7.06 (d, J=9.20 Hz, 1H), 6.83 (s, 1H), 5.22 (br s, 2H), 2.59 (s,3H).

Intermediate 17(1-[(tert-butoxy)carbonyl]-(±)-trans-4-ethylpyrrolidine-3-carboxylicacid)

Synthesised using a procedure similar to that described for Intermediate2 using ethyl (2E)-pent-2-enoate in step a. MS: ES+(M-56) 188.4, (M-100)142.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (br s, 1H), 3.47-3.55 (m,2H), 2.85-2.93 (m, 1H), 2.64-2.70 (m, 1H), 2.27-2.23 (m, 1H), 1.49-1.56(m, 1H), 1.39 (s, 9H), 1.27-1.34 (m, 2H), 0.86 (t, J=7.2 Hz, 3H).

Intermediate 181-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

Step a.

To a solution of 5-bromo-1H-indazole (2.00 g, 10.15 mmol) and1-bromo-2-methoxyethane (1.69 g, 12.19 mmol) in DMSO (20 ml) was addedCs₂CO₃ (8.22 g, 25.25 mmol) at rt. The reaction mixture was stirred atrt for 0.5 h. The resulting reaction mixture was diluted with water (50ml) and extracted with EtOAc (2×50 ml). The combined organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography(20% EtOAc in hexane) yielding 5-bromo-1-(2-methoxyethyl)-1H-indazole(1.20 g, 4.72 mmol). LCMS: Method A, 2.28 min, MS: ES+ 255.16.

Step b.

To a solution of 5-bromo-1-(2-methoxyethyl)-1H-indazole (0.30 g, 1.181mmol) in DMF were added bis(pinacolato)diboron (0.59 g, 2.36 mmol) andpotassium acetate (0.57 g, 5.90 mmol) at rt. The reaction mixture wasdegassed for 30 min. Pd(dppf)Cl₂.DCM complex (0.14 g, 0.17 mmol) wasadded to the reaction mixture at rt. The reaction mixture was heated at80° C. for 2 h. The resulting reaction mixture was diluted with water(30 ml) and extracted with EtOAc (3×30 ml). The combined organic phasewas dried over Na₂SO₄, filtered and concentrated under reduced pressure.The resulting residue was stirred in hexane (30 ml) for 10 min and thehexane layer was decanted (this process was repeated two more times) Thecombined hexane layer was concentrated under reduced pressure yielding1-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(0.41 g, quantitative). LCMS: Method A, 2.35 min, MS: ES+ 303.37.

Intermediate 19 Regioisomeric mixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylateand tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-carboxylate

Step a.

To a stirred solution of 4-bromo-1H-indazole (3.00 g, 15.22 mmol) in DCM(30 ml) were added DMAP (0.18 g, 1.52 mmol), TEA (1.84 g, 18.27 mmol)and BOC anhydride (3.7 ml, 16.75 mmol) at rt. The reaction mixturestirred at rt for 3 h, poured into water (100 ml) and extracted with DCM(3×30 ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography (20% EtOAc in hexane) yielding amixture in approximately 60:40 ratio of regio-isomers tert-butyl4-bromo-1H-indazole-1-carboxylate and tert-butyl4-bromo-2H-indazole-2-carboxylate (3.2 g, 10.77 mmol). LCMS: Method A,2.50 min, 2.61 min, MS: ES+ 297.14.

Step b.

The regioisomeric mixture of tert-butyl4-bromo-1H-indazole-1-carboxylate and tert-butyl4-bromo-2H-indazole-2-carboxylate prepared above (0.77 g, 2.59 mmol),bis (pinacolato) diboron (1.31 g, 5.18 mmol) and potassium acetate (1.27g, 12.96 mmol) in DMF (10 ml) was degassed for 30 min at rt. Pd(dppf)Cl₂(0.09 g, 0.13 mmol) was added to the reaction mixture at rt. Thereaction mixture was heated at 110° C. for 2 h. The resulting reactionmixture was poured in to water (50 ml) and extracted with EtOAc (3×30ml). The combined organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (20% EtOAc in hexane) yielding a regioisomericmixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylateand tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-carboxylate(0.45 g, 1.30 mmol). LCMS: Method A, 3.03 min, MS: ES+ 345.64.

Intermediate 20 tert-butyl (5-bromothiazol-2-yl)(4-methoxybenzyl)carbamate

Step a.

To a solution of 2-amino-5-bromothiazole (73.06 mmol) and DMAP (3.6mmol) in THF (130 ml) was added (BOC)₂O (73.06 mmol) at rt. The reactionmixture was stirred at rt for 6 h. Excess THF was removed under reducedpressure and the resulting residue was purified by column chromatography(0-5% EtOAc in Hexane) yielding tert-butyl(5-bromothiazol-2-yl)carbamate (52.1 mmol). MS: ES+ 279.08; ¹H NMR (400MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 7.44 (s, 1H), 1.48 (s, 9H).

Step b.

A mixture of tert-butyl (5-bromothiazol-2-yl)carbamate (3.6 mmol), PPh₃(7.9 mmol) and p-methoxybenzyl alcohol (7.2 mmol) in THF (10 ml) wascooled at 0° C. DIAD (7.9 mmol) was added dropwise to the reactionmixture at 0° C. The reaction mixture was stirred at 0° C. for 10 minand then at rt for 2 h. The resulting reaction mixture was concentratedunder reduced pressure and purified by flash chromatography (0-5% EtOAcin Hexane) yielding tert-butyl(5-bromothiazol-2-yl)(4-methoxybenzyl)carbamate (2.76 mmol). MS: ES− 56343.1; ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.57 (s, 1H), 7.22 (d, J=8.4 Hz,2H), 6.89 (d, J=8.4 Hz, 2H), 5.13 (s, 2H), 3.74 (s, 3H), 1.50 (s, 9H).

Intermediate 21 5-(4-fluorophenyl)-4-methylthiazol-2-amine

Step a.

To a stirred solution of 4-fluorophenyl acetone (3.28 mmol) in methanol(5 ml) were added thiourea (4.92 mmol) and Cu(OAc)₂ (0.33 mmol) at rt.The reaction mixture was stirred at rt for 30 min. Iodine (3.28 mmol)was added to the reaction mixture at rt and heated to 70° C. for 8 h.The resulting reaction mixture was cooled to rt and concentrated underreduced pressure to remove excess of methanol, saturated Na₂S₂O₃solution (30 ml) was added to the obtained concentrated mixture. Theresulting mixture was extracted with EtOAc (2×15 ml). The combinedorganic phase was collected, washed with brine (30 ml), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The obtainedresidue was triturated with diethyl ether (2×10 ml) yielding5-(4-fluorophenyl)-4-methylthiazol-2-amine (2.45 mmol). MS: ES+ 209.18;¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34-7.37 (m, 2H), 7.21 (t, J=9.2 Hz,2H), 7.01 (s, 2H), 2.15 (s, 3H).

Intermediate 22 5-(1-phenylethyl) thiazol-2-amine

Step a.

Bromine (2.0 mmol) was added dropwise to a solution of 3-phenylbutanal(2.0 mmol) in DCM (5 ml) at 0° C. The reaction mixture was stirred at rtfor 16 h. The resulting reaction mixture was concentrated under reducedpressure yielding 2-bromo-3-phenylbutanal. The obtained material wasused immediately for the next step without any further processing.

Step b.

Thiourea (3.5 mmol) was added to a solution of 2-bromo-3-phenylbutanal(1.76 mmol) in EtOH (7 ml) at rt. The reaction mixture was heated at 80°C. for 16 h. The resulting reaction mixture was cooled to rt andconcentrated under reduced pressure, water (10 ml) was added to theobtained concentrated mixture. The resulting mixture was extracted withEtOAc (3×20 ml). The combined organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure yielding5-(1-phenylethyl) thiazol-2-amine (1.71 mmol). This material was usedfor the next step without further purification. MS: ES+ 205.28

Intermediate 23 5-(4-fluorobenzyl)thiazol-2-amine

Synthesised using a procedure similar to that described for Intermediate22 using 3-(4-fluorophenyl)propionaldehyde in step a. MS: ES+ 209.18; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.22-7.31 (m, 2H), 7.09-7.15 (m, 2H), 6.72(br s, 2H), 6.69 (s, 1H), 3.92 (s, 2H).

Intermediate 24 tert-butyl (2′-amino-[4,4′-bipyridin]-2-yl)carbamate

Step a.

A mixture of tert-butyl (4-bromopyridin-2-yl)carbamate (0.19 g, 0.68mmol) in 1,4-dioxane:water (8:2) (10 ml) was prepared in a glass vial.The reaction mixture was degassed for 15 min. 2-Aminopyridine-4-boronicacid pinacol ester (0.15 g, 0.68 mmol) and K₃PO₄ (0.43 g, 2.04 mmol)were added to the reaction mixture at rt. The reaction mixture wasdegassed again for 15 min. Pd(dppf)Cl₂ (0.024 g, 0.034 mmol). The glassvial was sealed and subjected to heating at 110° C. (externaltemperature) for 2 h. The resulting reaction mixture was combined withone other batch on the same scale prepared by an identical method,poured into water (50 ml) and extracted with EtOAc (2×30 ml). Thecombined organic phase was washed with brine (20 ml), dried over Na₂SO₄,filtered and concentrated under reduced pressure yielding tert-butyl(2′-amino-[4,4′-bipyridin]-2-yl)carbamate (0.50 g, quantitative). LCMS:Method A, 1.71 min, MS: ES+ 287.48.

Intermediate 25 tert-butyl (2′-amino-[4,4′-bipyridin]-2-yl)(methyl)carbamate

Step a.

To a solution of tert-butyl (4-bromopyridin-2-yl)carbamate (0.25 g,0.915 mmol) in DMF (5 ml) was added NaH (60% in oil) (0.073 g, 1.83mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min.Methyl iodide (0.26 g, 1.37 mmol) was added to the reaction mixture at0° C. The reaction mixture was stirred at rt for 1 h, poured into icecold water (20 ml) and extracted with EtOAc (2×15 ml). The organic layerwas washed with brine (20 ml). The organic phase was collected, driedover Na₂SO₄, filtered and concentrated under reduced pressure yieldingtert-butyl (4-bromopyridin-2-yl)(methyl)carbamate (0.25 g, 0.87 mmol).This material was directly used for the next step without furtherpurification. LCMS: Method A, 2.50 min, MS: ES+ 230.9; 232.9 (M-56)

Step b.

A procedure similar to that described for Intermediate 24 was used toafford the title compound LCMS: Method A, 1.71 min, MS: ES+ 301.37

Intermediate 26 3-amino-N-methylisoquinoline-6-carboxamidetrifluoracetic acid salt

Step a.

LiHMDS (1M in Hexane) (18 ml, 18.02 mmol) was added dropwise to astirred solution of 6-bromoisoquinolin-3-amine (2.00 g, 9.01 mmol) inTHE (40 ml) at −40° C. The resulting reaction mixture was stirred at 0°C. temperature for 30 min. A solution of BOC anhydride (1.96 g, 9.01mmol) in THF (10 ml) at 0° C. was added dropwise to the reactionmixture. The reaction mixture was stirred at rt for 1 h and then pouredinto NH₄Cl solution (80 ml) and extracted with EtOAc (3×80 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding tert-butyl(6-bromoisoquinolin-3-yl)carbamate (2.87 g, 8.91 mmol). LCMS: Method A,2.64 min, MS: ES+ 323.19.

Step b.

A mixture of tert-butyl (6-bromoisoquinolin-3-yl)carbamate (2.80 g, 8.69mmol), sodium acetate (3.56 g, 43.48 mmol) and Pd(dppf)Cl₂.DCM complex(3.55 g, 4.35 mmol) in MeOH (60 ml) was taken in a pressure vessel. Theresulting reaction mixture was stirred at 85° C. under a pressure of CO(25 kg/cm²) for 48 h. The resulting reaction mixture was filtered andthe filtrate was concentrated under reduced pressure. The residue wassuspended in DCM and filtered. The filtrate was concentrated underreduced pressure and the resulting residue was purified bychromatography (1% MeOH in DCM) yielding methyl3-((tert-butoxycarbonyl)amino) isoquinoline-6-carboxylate (2.40 g, 7.95mmol). LCMS: Method A, 2.43 min, MS: ES+ 303.

Step c.

A solution of NaOH (0.70 g, 17.38 mmol) in 50 ml water was added to asolution of methyl3-((tert-butoxycarbonyl)amino)isoquinoline-6-carboxylate (1.75 g, 5.79mmol) in methanol (50 ml) at rt. The reaction mixture was heated at 70°C. for 4 h. The resulting reaction mixture was allowed to cool to rt andacidified by slow addition of citric acid solution under continuousstirring. The resulting mixture was extracted with EtOAc (3×100 ml). Thecombined organic phase was collected dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding3-((tert-butoxycarbonyl)amino)isoquinoline-6-carboxylic acid (1.80 g,quantitative). LCMS: Method A, 2.12 min, MS: ES+ 289.33.

Step d.

A mixture of 3-((tert-butoxycarbonyl)amino)isoquinoline-6-carboxylicacid (1.80 g, 6.25 mmol), HATU (3.56 g, 9.37 mmol) and DIPEA (2.15 ml,12.50 mmol) in THF (50 ml) was prepared at 0° C. The reaction mixturewas stirred at rt for 0.5 h. Methyl amine (2M in THF) (6.25 ml, 12.50mmol) was added in to the reaction mixture at rt. The reaction mixturewas stirred at rt for 18 h. The resulting reaction mixture was pouredinto saturated NaHCO₃ solution (100 ml) and extracted with EtOAc (3×100ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography (3% MeOH in DCM) yieldingtert-butyl (6-(methylcarbamoyl)isoquinolin-3-yl)carbamate (1.35 g, 4.48mmol). LCMS: Method A, 2.01 min, MS: ES+ 302.38.

Step e.

To a solution of tert-butyl(6-(methylcarbamoyl)isoquinolin-3-yl)carbamate (1.30 g, 4.318 mmol) inDCM (50 ml) was added TFA (13 ml) at 0° C. The reaction mixture wasstirred at rt for 2 h. The resulting reaction mixture was concentratedunder reduced pressure yielding3-amino-N-methylisoquinoline-6-carboxamide TFA salt (2.0 g,quantitative).

LCMS: Method A, 0.89 min, MS: ES+ 202.13.

Intermediate 27 tert-butyl(2S,3S)-3-((6-(1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)-2-methylpyrrolidine-1-carboxylate

Step a.

To a solution of 6-bromoisoquinolin-3-amine (0.20 g, 0.89 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.19 g,0.98 mmol) in DMF:water (4:1, 5 ml) was prepared in a microwave glassvial. Cs₂CO₃ (0.87 g, 2.68 mmol) was added to the reaction mixture atrt. The reaction mixture was degassed at rt for 15 min before addingPd(dppf)Cl₂ (0.06 g, 0.09 mmol) and the glass vial was sealed. Thereaction mixture was subjected to microwave heating at 150° C. for 1 h.The resulting reaction mixture was poured into water (50 ml) andextracted with EtOAc (3×50 ml). The combined organic layer was washedwith brine solution (50 ml), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (2.2% MeOH in DCM) yielding 6-(1H-pyrazol-4-yl)isoquinolin-3-amine (0.11 g, 0.52 mmol).

LCMS: Method A, 1.47 min, MS: ES+ 211.18.

Step b.

To a solution of 6-(1H-pyrazol-4-yl) isoquinolin-3-amine (0.09 g, 0.42mmol) and Intermediate 1 (0.10 g, 0.42 mmol) in DCM (2 ml) was addedpyridine (0.9 ml g) at 0° C. POCl₃ (0.08 g, 0.51 mmol) was addeddropwise to the reaction mixture at 0° C. The reaction mixture wasstirred at 0° C. for 15 min and then at rt for 30 min. The resultingreaction mixture was diluted with cold water (30 ml) and extracted withEtOAc (3×30 ml). The combined organic layer was washed with saturatedaqueous solution of citric acid (30 ml), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (1.2% MeOH in DCM) yielding tert-butyl(2S,3S)-3-((6-(1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)-2-methylpyrrolidine-1-carboxylate(0.045 g, 0.10 mmol). LCMS: Method A, 1.96 min, MS: ES+ 422.52.

Intermediate 28 6-(oxazol-5-yl)imidazo[1,2-a]pyridin-2-amine

Step a.

To a suspension of LiAlH₄ powder (0.165 g, 4.35 mmol) in THF (10 ml) wasadded a solution of methyl2-(2,2,2-trifluoroacetamido)imidazo[1,2-a]pyridine-6-carboxylate (0.5 g,1.74 mmol) in THF (5 ml) dropwise at 0° C. under nitrogen atmosphere.The reaction mixture was stirred at 0° C. under nitrogen atmosphere for1 h. The resulting reaction mixture was combined with one other batch onthe same scale prepared by an identical method and quenched in EtOAc(100 ml). The resulting organic solution was washed with water (50 ml).The emulsion was filtered through celite hyflow. The organic phase wasseparated from the filtrate. The resulting organic phase was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was triturated with n-pentane (2×10 ml) and dried to yield2,2,2-trifluoro-N-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)acetamide(0.55 g, 2.12 mmol). LCMS: Method A, 1.57 min, MS: ES+ 260.21.

Step b.

To a solution of2,2,2-trifluoro-N-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)acetamide(0.55 g, 2.12 mmol) in DCM (20 ml) was added Dess-Martin periodinane(3.6 g, 8.49 mmol) at rt. The reaction mixture was stirred at rt for 2days. The resulting reaction mixture was combined with one other batchwhich was performed at 0.25 g scale following an identical method. Theresulting reaction mixture was carefully filtered through celite hyflow.The resulting filtrate was poured in to water (200 ml), basified withsolid NaHCO₃ and extracted with EtOAc (2×100 ml). The combined organicphase was collected dried over Na₂SO₄, filtered and concentrated underreduced pressure. The obtained residue was triturated with n-hexane (3×7ml) and dried yielding2,2,2-trifluoro-N-(6-formylimidazo[1,2-a]pyridin-2-yl)acetamide (0.75 g,2.92 mmol). LCMS: Method A, 1.85 min, MS: ES+ 258.36.

Step c.

A mixture of2,2,2-trifluoro-N-(6-formylimidazo[1,2-a]pyridin-2-yl)acetamide (0.75 g,2.92 mmol), 4-toluenesulphonylmethyl isocyanide (0.569 g, 2.92 mmol) andK₂CO₃ (0.805 g, 5.83 mmol) in MeOH (10 ml) was heated to 70° C. for 3 h.The resulting reaction mixture was poured into water (150 ml) andextracted with EtOAc (3×70 ml). The combined organic phase was driedover Na₂SO₄, filtered and concentrated under reduced pressure yielding2,2,2-trifluoro-N-(6-(oxazol-5-yl)imidazo[1,2-a]pyridin-2-yl)acetamide(0.55 g, 1.86 mmol). This material was used directly for the next stepwithout further purification. LCMS: Method A, 1.88 min, MS: ES+ 297.38.

Step d.

To a solution of2,2,2-trifluoro-N-(6-(oxazol-5-yl)imidazo[1,2-a]pyridin-2-yl)acetamide(0.25 g, 0.844 mmol) in water was added NaOH (0.13 g, 3.375 mmol) at rt.The reaction mixture was stirred at rt for 2 h. The resulting reactionmixture was poured into water (120 ml) and extracted with EtOAc (2×20ml). The combined organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding6-(oxazol-5-yl)imidazo[1,2-a]pyridin-2-amine (0.17 g, 0.84 mmol). Thismaterial was used directly for the next step without furtherpurification.

Intermediate 296-(isopropylsulfonyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-amine

Step a.

To a solution of 4-perhydroazepinone hydrochloride (1 g, 6.68 mmol) inDCM (10 ml) was added DIPEA (3.45 g, 26.73 mmol) at rt for 10 min.Isopropylsulfonyl chloride (1.14 g, 8.02 mmol) was added to the reactionmixture at rt. The reaction mixture was stirred at rt for 2 h. Theresulting reaction mixture was poured into water (100 ml) and extractedwith DCM (3×40 ml). The organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure to1-(isopropylsulfonyl)azepan-4-one (0.54 g, 2.46 mmol). This material wasused directly for the next step without further purification. LCMS:Method A, 1.54 min, MS: ES+ 220.23.

Step b.

To a solution of 1-(isopropylsulfonyl)azepan-4-one (0.54 g, 2.46 mmol)in CHCl₃ (10.8 ml) was added bromine (0.29 g, 3.6 mmol) at 0° C. Thereaction mixture was stirred at rt for 1 h. The resulting reactionmixture was poured into sodium metabisulphite solution (60 ml) andextracted with DCM (3×30 ml). The combined organic phase was dried overNa₂SO₄, filtered and concentrated under reduced pressure to yielding5-bromo-1-(isopropylsulfonyl)azepan-4-one (0.6 g, 2.02 mmol). Thismaterial was used directly for the next step without furtherpurification.

Step c.

To a solution of 5-bromo-1-(isopropylsulfonyl)azepan-4-one (0.6 g, 2.02mmol) in ethanol (9 ml) was added thiourea (0.76 g, 10.10 mmol) at rt.The reaction mixture was heated at 90° C. for 2 h. The resultingreaction mixture was poured into 1M HCl solution (50 ml) and extractedwith DCM (2×20 ml). The aqueous layer was neutralised with solid Na₂CO₃to adjust pH up to 8 and extracted with DCM (3×30 ml). The combinedorganic phase was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography (2% MeOH in DCM) yielding 6-(isopropylsulfonyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-amine (0.18 g,0.67 mmol). LCMS: Method C, 3.03 min, MS: ES+ 276.05

Intermediate 30 1-(4-(1-(2-methoxyethyl)-1H-pyrazol)-1H-imidazol-4-amine

Step a.

To a solution of 1,4-dinitro-1H-imidazole (2.5 g, 15.80 mmol) in MeOH(40 ml) was added 4-bromoaniline (2.70 g, 15.80 mmol) at 0° C. Thereaction mixture was stirred at rt for 16 h. The resulting solidprecipitates were collected by filtration under reduced pressure anddried yielding 1-(4-bromophenyl)-4-nitro-1H-imidazole (3.5 g, 13.11mmol). This material was used directly for the next step without furtherpurification. LCMS: Method A, 2.11 min, MS: ES+ 268.20.

Step b.

A solution of 1-(4-bromophenyl)-4-nitro-1H-imidazole (0.30 g, 1.12 mmol)and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.26 g,1.35 mmol) in DMF water (9:1, 10 ml) was prepared in a microwave glassvial. Na₂CO₃ (0.23 g, 2.24 mmol) was added to the reaction mixture atrt. The reaction mixture was degassed for 30 min at rt. Pd(dppf)Cl₂.DCMcomplex (0.10 g, 0.11 mmol) was added to the reaction mixture at rt. Thereaction mixture was subjected to microwave heating at 150° C. for 1 h.The resulting reaction mixture was poured into water (20 ml) andextracted with EtOAc (3×20 ml). The combined organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was triturated with n-pentane (30 ml) yielding4-(4-(4-nitro-1H-imidazol-1-yl) phenyl)-1H-pyrazole (0.25 g, 0.98 mmol).This material was used directly for the next step without furtherpurification. LCMS: Method A, 1.78 min, MS: ES+ 256.41.

Step c.

To a solution of (4-(4-(4-nitro-1H-imidazol-1-yl) phenyl)-1H-pyrazole(0.23 g, 0.90 mmol) in DMF (6 ml) was added K₂CO₃ (0.37 g, 2.70 mmol) atrt. The reaction mixture was stirred at rt for 5 min and treated with1-bromo-2-methoxyethane (0.19 g, 1.35 mmol). The reaction mixture washeated at 100° C. for 16 h. The resulting reaction mixture allowed tocool to rt, poured into water (15 ml) and extracted with EtOAc (3×10ml). The combined organic phase was collected, washed with water (2×10ml), dried over Na₂SO₄, filtered and concentrated under reduced pressureyielding1-(2-methoxyethyl)-4-(4-(4-nitro-1H-imidazol-1-yl)phenyl)-1H-pyrazole(0.25 g, 0.79 mmol). This material was used directly for the next stepwithout further purification. LCMS: Method A, 1.91 min, MS: ES+ 314.59.

Step d.

To a solution of1-(2-methoxyethyl)-4-(4-(4-nitro-1H-imidazol-1-yl)phenyl)-1H-pyrazole(0.25 g, 0.79 mmol) in THF (5 ml) was added 10% Pd/C (0.05 g) at rt. Thereaction mixture was purged with H₂ gas at rt for 2 h. The resultingreaction mixture was carefully filtered through celite hyflow. Theobtained filtrate was directly used for next acid amine couplingreaction. LCMS: Method A, 1.41 min, MS: ES+ 284.39.

Intermediate 31(3S,4R)-1-(tert-butoxycarbonyl)-4-(pyridin-3-yl)pyrrolidine-3-carboxylicacid

Synthesised using a procedure similar to that described for Intermediate2 using ethyl trans-3-(3-pyridyl)acrylate in step a. LCMS: Method A,1.51 min, MS: ES+ 293.28; ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.5 (br s,1H), 8.55 (d, J=2 Hz, 1H), 8.47 (dd, J=1.6 Hz, 4.8 Hz, 1H), 7.84 (d,J=7.6 Hz, 1H), 7.37-7.40 (m, 1H), 3.72-3.80 (m, 2H), 3.48-3.61 (m, 1H),3.36-3.45 (m, 1H), 3.23-3.28 (m, 1H), 2.64-2.78 (m, 1H), 1.38 (s, 9H).

Intermediate 32(3S,4R)-1-(tert-butoxycarbonyl)-4-(pyrimidin-5-yl)pyrrolidine-3-carboxylicacid

Synthesised using a procedure similar to that described for Intermediate2 using 3-pyrimidin-5-yl-acrylic acid ethyl ester in step a. LCMS:Method A, 1.65 min, MS: ES+ 294.23; ¹H NMR (400 MHz, DMSO-d6) δ ppm12.47 (br s, 1H), 9.08 (s, 1H), 8.83 (s, 2H), 3.78-3.83 (m, 1H),3.59-3.53 (m, 2H), 3.51-3.46 (m, 2H), 2.78-2.64 (m, 1H), 1.43 (s, 9H).

Intermediate 331-(tert-butoxycarbonyl)-3-methoxypyrrolidine-3-carboxylic acid

Step a.

To a solution of tert-butyl 3-cyano-3-hydroxypyrrolidine-1-carboxylate(0.60 g, 2.83 mmol) in MeOH (15 ml) was added 4M HCl in 1,4-dioxane (6ml) at 0° C. The reaction mixture was stirred at rt for 1 h. Theresulting reaction mixture was concentrated under reduced pressureyielding methyl 3-hydroxypyrrolidine-3-carboxylate HCl salt (0.55 g,quantitative). This material was used directly for next step withoutfurther purification.

LCMS: Method A, 0.25 min, MS: ES+ 146.08.

Step b.

To the suspension of methyl 3-hydroxypyrrolidine-3-carboxylate HCl (0.55g, 3.03 mmol) in sat. NaHCO₃ solution (2 ml) and EtOAc (5 ml) was addedBOC anhydride (1.32 g, 6.07 mmol) and stirred at rt for 8 h. Theresulting reaction mixture was poured into water (15 ml) and extractedwith EtOAc (3×10 ml). The combined organic phase was collected, driedover Na₂SO₄, filtered and concentrated under reduced pressure yielding1-(tert-butyl) 3-methyl 3-hydroxypyrrolidine-1,3-dicarboxylate (0.29 g,1.18 mmol). This material was used directly for the next step withoutfurther purification. LCMS: Method A, 1.88 min, MS: ES+ 246.30.

Step c.

To a solution of methyl 1-(tert-butyl) 3-methyl3-hydroxypyrrolidine-1,3-dicarboxylate (0.27 g, 1.10 mmol) in MeCN (10ml) was added Cs₂CO₃ (1.79 g, 5.51 mmol) at rt. The reaction mixture wasstirred at rt for 5 min. CH₃I (0.78 g, 5.51 mmol) was added to thereaction mixture at rt. The reaction mixture was heated at 80° C. for 20h. The resulting reaction mixture was poured into cold water (15 ml) andextracted with EtOAc (3×10 ml). The combined organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by column chromatography(10% EtOAc in hexane) yielding 1-(tert-butyl) 3-methyl3-methoxypyrrolidine-1,3-dicarboxylate (0.23 g, 0.88 mmol). LCMS: MethodA, 2.13 min, MS: ES+ 260.30.

Step d.

To a solution of 1-(tert-butyl) 3-methyl3-methoxypyrrolidine-1,3-dicarboxylate (0.23 g, 0.88 mmol) in MeOH (10ml) was added LiOH.H₂O (0.15 g, 3.55 mmol) at rt. The reaction mixturewas stirred at rt for 2 h. The resulting reaction mixture was dilutedwith water (10 ml) and extracted with EtOAc (2×10 ml). The aqueous layerwas acidified to pH 6 using 10% aqueous solution of citric acid. Theresulting mixture was extracted with MeOH: EtOAc mixture (1:9, 7×10 ml).The combined organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding1-(tert-butoxycarbonyl)-3-methoxypyrrolidine-3-carboxylic acid (0.20 g,0.81 mmol). This material was directly used for the next step withoutfurther purification. LCMS: Method A, 1.85 min, MS: ES− 244.20.

Intermediate 34 2′-chloro-[4,4′-bipyridin]-2-amine

Step a.

A mixture of 2-chloro-4-iodopyridine (0.75 g, 3.13 mmol),2-aminopyridine-4-boronic acid pinacol ester (0.76 g, 3.45 mmol) andK₃PO₄ (1.3 g, 6.26 mmol) was prepared in 1,4-dioxane:water (2:1, 3 ml)at rt. The reaction mixture was degassed for 15 min. PdCl₂(dppf) (0.11g, 0.16 mmol) was added to the reaction mixture at rt. The reactionmixture was heated at 100° C. for 16 h. The resulting reaction mixturewas allowed to cool to rt, poured into brine solution (100 ml) andextracted with EtOAc (3×75 ml). The combined organic phase was washedwith DM water (75 ml). The organic phase was separated, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by flash chromatography (75% EtOAc in hexane)yielding 2′-chloro-[4,4′-bipyridin]-2-amine (0.3 g, 1.46 mmol). LCMS:Method A, 1.49 min, MS: ES+ 206.13.

Intermediate 35 4-amino-2-cyclopropylbenzonitrile

Step a.

A solution of 4-amino-2-chlorobenzonitrile (0.46 g, 3.00 mmol) andcyclopropylboronic acid (0.39 g, 4.50 mmol) in toluene:water (6:1, 7 ml)was prepared in a glass vial at rt. K₃PO₄ (2.55 g, 12.01 mmol) andtricyclohexylphosphine (0.34 g, 1.20 mmol) were added to the reactionmixture at rt under nitrogen atmosphere. The reaction mixture was purgedwith nitrogen for 15 min. Pd(OAc)₂ (0.13 g, 0.6 mmol) was added to thereaction mixture at rt under nitrogen atmosphere. The glass vial wassealed and the reaction mixture was heated at 80° C. for 15 h. Theresulting reaction mixture was poured into water (200 ml) and extractedwith EtOAc (3×100 ml). The combined organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography (25% EtOAc in Hexane) yielding4-amino-2-cyclopropylbenzonitrile (0.34 g, 2.15 mmol). LCMS: Method A,1.90 min, MS: ES+ 159.3.

Example 1 (S)-1-cyano-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 1)

Step a.

A solution of 5-phenylthiazol-2-amine (2.6 mmol) and(3S)-BOC-1-pyrrolidine-3-carboxylic acid (2.9 mmol) in THF was stirredat 0° C. for 5 min. To this solution was added T3P (50% in EtOAc) (3.9mmol) and DIPEA (5.2 mmol) at 0° C. The reaction mixture was stirred atrt for 1 h. The resulting reaction mixture was poured into water (40 ml)and extracted with DCM (40 ml). The organic phase was collected andwashed with 1M NaOH solution (30 ml), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (2-3% MeOH in DCM) yielding tert-butyl(S)-3-((5-phenylthiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate (1.2mmol). MS: ES+ 374.13; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.37 (br s, 1H),7.89 (s, 1H), 7.60-7.62 (m, 2H), 7.40-7.43 (m, 2H), 7.28-7.32 (m, 1H),3.51-3.53 (m, 1H), 3.36-3.43 (m, 2H), 3.22-3.31 (m, 2H), 2.12-2.18 (m,1H), 2.01-2.09 (m, 1H), 1.37-1.43 (m, 9H).

Step b.

To a solution of tert-butyl(S)-3-((5-phenylthiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate (1.2mmol) in DCM (10 ml) was added 4M HCl in EtOAc (40 mmol) at 0° C. Thereaction mixture was stirred at rt for 4 h. The resulting reactionmixture was concentrated under reduced pressure. The obtained residuewas triturated with diethyl ether (10 ml) yielding(S)—N-(5-phenylthiazol-2-yl) pyrrolidine-3-carboxamide hydrochloride(1.28 mmol). MS: ES+ 274.13; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.55 (brs, 1H), 9.58 (br s, 1H), 9.34 (br s, 1H), 7.91 (s, 1H), 7.60-7.62 (m,2H), 7.40-7.44 (m, 2H), 7.29-7.33 (m, 1H), 3.38-3.44 (m, 3H), 3.19-3.24(m, 2H), 2.25-2.33 (m, 1H), 2.08-2.12 (m, 1H).

Step c.

To a solution of (S)—N-(5-phenylthiazol-2-yl) pyrrolidine-3-carboxamidehydrochloride (1.2 mmol) in DCM (5 ml) was added K₂CO₃ (2.4 mmol) andcyanogen bromide (2.4 mmol) at 0° C. The reaction mixture was stirred atrt for 16 h. The resulting reaction mixture was poured into water (40ml) and extracted with DCM (50 ml). The organic phase was collected,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography (1-1.5% MeOH inDCM) yielding the title compound (0.77 mmol). MS: ES+ 299.0; ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.43 (s, 1H), 7.90 (s, 1H), 7.61-7.63 (m, 2H),7.40-7.44 (m, 2H), 7.29-7.33 (m, 1H), 3.63-3.66 (m, 1H), 3.53-3.61 (m,1H), 3.42-3.49 (m, 2H), 3.33-3.40 (m, 1H), 2.16-2.23 (m, 1H), 2.06-2.12(m, 1H).

Compounds in Table 1 were synthesised using a procedure similar to thatdescribed for Example 1 using 1-BOC-pyrrolidine-3-carboxylic acid

TABLE 1 Amine CAS ¹H NMR (400 MHz, Ex R1 Name Number DMSO-d₆) δ ppm MS 2

1-cyano-N- (5-(3- fluorophenyl) thiazol-2- yl)pyrrolidine-3- carboxamide438585-95-6 12.49 (s, 1 H), 8.00 (s, 1 H), 7.51-7.56 (m, 1 H), 7.41-7.51 (m, 2 H), 7.10-7.18 (m, 1 H), 3.61-3.67 (m, 1 H), 3.53-3.59 (m, 1H), 3.42- 3.49 (m, 2 H), 3.35-3.41 (m, 1 H), 2.16-2.26 (m, 1 H),2.05-2.14 (m, 1 H) ES+ 317.18 3

1-cyano-N-(5- (2-fluorophenyl) thiazol-2- yl)pyrrolidine-3- carboxamide1025927-65-4 12.49 (s, 1 H), 7.97 (s, 1 H), 7.79 (t, J = 7.24 Hz, 1 H),7.33-7.40 (m, 2 H), 7.25-7.31 (m, 1 H), 3.61-3.67 (m, 1 H), 3.54-3.58(m, 1 H), 3.43- 3.50 (m, 2 H), 3.36-3.41 (m, 1 H), 2.17-2.23 (m, 1 H),2.06-2.11 (m, 1 H) ES+ 317.18 4

N-(5-(4- chlorophenyl)thiazol- 2-yl)-1- cyanopyrrolidine- 3-carboxamide73040-66-1 12.47 (s, 1 H), 7.95 (s, 1 H), 7.65 (d, J = 8.54 Hz, 2 H),7.48 (d, J = 8.54 Hz, 2 H), 3.60-3.65 (m, 1 H), 3.53-3.57 (m, 1 H),3.42-3.50 (m, 2 H), 3.36-3.42 (m, 1 H), 2.16-2.23 (m, 1 H), 2.05-2.12(m, 1 H) ES+ 333.13 5

N-(5-(3- chlorophenyl)thiazol- 2-yl)-1- cyanopyrrolidine-3- carboxamide1249447-08-2 12.50 (s, 1 H), 8.02 (s, 1 H), 7.74 (t, J = 1.83 Hz, 1 H),7.56 (d, J = 7.60 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.8Hz, 1 H), 3.61- 3.67 (m, 1 H), 3.53-3.59 (m, 1 H), 3.42-3.49 (m, 2 H),3.36-3.42 (m, 1 H), 2.16-2.26 (m, 1 H), 2.04-2.14 (m, 1 H) ES+ 332.88 6

N-(5-(2- chlorophenyl)thiazol- 2-yl)-1- cyanopyrrolidine-3- carboxamideIntermediate 10 12.49 (s, 1 H), 7.81 (s, 1 H), 7.66-7.68 (m, 1 H), 7.58-7.61 (m, 1 H), 7.37-7.45 (m, 2 H), 3.60-3.67 (m, 1 H), 3.53-3.60 (m, 1H), 3.42- 3.50 (m, 2 H), 3.32-3.42 (m, 1 H), 2.15-2.25 (m, 1 H),2.04-2.15 (m, 1 H) ES+ 332.88 7

1-cyano-N-(5- methylthiazol-2- yl)pyrrolidine-3- carboxamide 7305-71-712.13 (s, 1 H), 7.14 (d, J = 1.20 Hz, 1 H), 3.58-3.63 (m, 1 H),3.48-3.52 (m, 1 H), 3.39-3.47 (m, 2 H), 3.25-3.32 (m, 1 H), 2.34 (d, J =1.22 Hz, 3 H), 2.13-2.22 (m, 1 H), 1.99-2.09 (m, 1 H) ES+ 237.01 8

N-(5-(tert- butyl)thiazol-2-yl)- 1-cyanopyrrolidine- 3-carboxamide299417-31-5 12.13 (s, 1 H), 7.17 (s, 1 H), 3.60-3.62 (m, 1 H), 3.48-3.58 (m, 1 H), 3.39-3.47 (m, 2 H), 3.25-3.32 (m, 1 H), ES+ 279.932.14-2.19 (m, 1 H), 2.06- 2.09 (m, 1 H), 1.32 (s, 9 H) 9

1-cyano-N-(4- phenylthiazol-2- yl)pyrrolidine-3- carboxamide 2010-06-212.50 (s, 1 H), 7.89-7.91 (m, 2 H), 7.66 (s, 1 H), 7.41-7.45 (m, 2 H),7.31-7.35 (m, 1 H), 3.60-3.71 (m, 1 H), 3.52- 3.60 (m, 1 H), 3.41-3.52(m, ES+ 299.43 2 H), 3.32-3.42 (m, 1 H), 2.18-2.23 (m, 1 H), 2.06- 2.13(m, 1 H) 10

1-cyano-N-(2- phenylthiazol-5- yl)pyrrolidine-3- carboxamide 87657-91-811.69 (s, 1 H), 7.85-7.88 (m, 2 H), 7.61 (s, 1 H), 7.40-7.49 (m, 3 H),3.61-3.65 (m, 1 H), 3.52-3.58 (m, 1 H), 3.40-3.51 (m, 2 H), 3.22-3.32(m, 1 H), ES+ 298.90 2.16-2.24 (m, 1 H), 2.03-2.11 (m, 1 H) 11

1-cyano-N-(5- phenyl-1,3,4- thiadiazol-2- yl)pyrrolidine-3- carboxamide2002-03-1 12.90 (s, 1 H), 7.94-7.95 (m, 2 H), 7.54-7.55 (m, 3 H),3.56-3.68 (m, 2 H), 3.33- 3.47 (m, 3 H), 2.19-2.25 (m, 1 H), 2.08-2.14(m, 1 H) ES+ 299.96 12

1-cyano-N-(5-ethyl- 1,3,4-thiadiazol-2- yl)pyrrolidine-3- carboxamide14068-53-2 13.84 (br s, 1 H), 3.84-3.89 (m, 1 H), 3.64-3.79 (m, 3 H),3.55-3.61 (m, 1 H), 3.07- 3.12 (m, 2H), 2.39-2.47 (m, ES+ 252.10 1 H),2.27-2.36 (m, 1 H), 1.45 (t, J = 7.48 Hz, 3 H) 13

1-cyano-N-(3- phenylisoxazol-5- yl)pyrrolidine-3- carboxamide 4369-55-511.96 (s, 1 H), 7.83-7.89 (m, 2 H), 7.48-7.55 (m, 3 H), 6.77 (s, 1 H),3.54-3.64 (m, 2 H), 3.42-3.46 (m, 2 H), 3.24-3.33 (m, 1 H), 2.16-2.26ES+ 282.93 (m, 1 H), 2.06-2.12 (m, 1 H) 14

1-cyano-N-(3-(4- methoxyphen- yl)isoxazol-5- yl)pyrrolidine-3-carboxamide 86685-98-5 11.90 (s, 1 H), 7.79 (d, J = 9.15 Hz, 2 H), 7.04(d, J = 8.85 Hz, 2 H), 6.72 (s, 1 H), 3.81 (s, 3 H), 3.59-3.66 (m, 1 H),3.52-3.60 (m, 1 H), 3.40-3.49 (m, 2 H), 3.26- 3.21 (m, 1 H), 2.14-2.25(m, 1 H), 2.03-2.13 (m, 1 H) ES+ 312.97 15

1-cyano-N-(5- phenylisoxazol-3- yl)pyrrolidine-3- carboxamide 6455-31-811.31 (s, 1 H), 7.88-7.90 (m, 2 H), 7.52-7.57 (m, 3 H), 7.39 (s, 1 H),3.59-3.65 (m, 1 H), 3.51-3.57 (m, 1 H), 3.41-3.49 (m, 2 H), 3.25-3.32ES+ 282.93 (m, 1 H), 2.15-2.24 (m, 1 H), 2.02-2.12 (m, 1 H) 16

N-(5-(tert- butyl)isoxazol-3-yl)- 1-cyanopyrrolidine- 3-carboxamide55809-36-4 11.18 (s, 1 H), 6.62 (s, 1 H), 3.55-3.61 (m, 1 H), 3 .46-3.51 (m, 1 H), 3.38-3.45 (m, 2 H), 3.21-3.24 (m, 1 H), 2.12-2.17 (m, 1H), 1.99- ES+ 263.0 2.07 (m, 1 H), 1.29 (s, 9 H) 17

N-(3-(tert-butyl)-1H- pyrazol-5-yl)-1- cyanopyrrolidine-3- carboxamide82560-12-1 12.07 (br s, 1 H), 10.50 (s, 1 H), 6.30 (s, 1 H), 3.55-3.58(m, 1 H), 3.33-3.49 (m, 3 H), 3.14-3.19 (m, 1 H), 2.06-2.16 (m, 1 H),1.94-2.05 (m, ES+ 262.04 1 H), 1.25 (s, 9 H) 18

N-(benzo[d]thiazol- 2-yl)-1-cyano- pyrrolidine-3- carboxamide 136-95-812.57 (s, 1 H), 7.99 (d, J = 7.20 Hz, 1 H), 7.76 (d, J = 7.94 Hz, 1 H),7.42-7.47 (m, 1 H), 7.30-7.34 (m, 1 H), 3.56-3.68 (m, 2 H), 3.35- 3.50(m, 3 H), 2.19-2.26 (m, ES+ 273.10 1 H), 2.06-2.16 (m, 1 H) 19

1-cyano-N-(6- methylbenzo[d]thiazol- 2-yl)pyrrolidine-3- carboxamide2536-91-6 10.32 (br s, 1 H), 7.64-7.68 (m, 2 H), 7.31 (dd, 8.4 Hz, 1.2Hz, 1 H), 3.76-3.81 (m, 1 H), 3.63-3.71 (m, 2 H), 3.44-3.50 (m, 1 H),3.17- 3.20 (m, 1 H), 2.51 (s, 3 H), ES+ 287.18 2.19-2.36 (m, 2 H) 20

1-cyano-N-(6-(trifluoro- methyl)benzo[d]thiazol- 2-yl)pyrrolidine-3-carboxamide 777-12-8 12.84 (s, 1 H), 8.54 (s, 1 H), 7.93 (d, J = 8.24Hz, 1 H), 7.76 (d, J = 8.85 Hz, 1 H), 3.57-3.69 (m, 2 H), 3.38- 3.50 (m,3 H), 2.19-2.29 (m, 1 H), 2.07-2.17 (m, 1 H) ES+ 340.84 21

1-cyano-N-(6-methoxy- benzo[d]thiazol-2- yl)pyrrolidine-3- carboxamide1747-60-0 12.44 (s, 1 H), 7.65 (d, J = 8.85 Hz, 1 H), 7.59 (d, J = 2.44Hz, 1 H), 7.04 (dd, J = 8.69, 2.59 Hz, 1 H), 3.81 (s, 3 H), 3.61-3.68(m, 1 H), 3.53-3.60 (m, 1 H), 3.41- ES+ 303.10 3.52 (m, 2 H), 3.35-3.41(m, 1 H), 2.16-2.28 (m, 1 H), 2.03-2.15 (m, 1 H) 22

N-(6- bromobenzo[d]thiazol- 2-yl)-1- cyanopyrrolidine-3- carboxamide15864-32-1 12.67 (s, 1 H), 8.28 (d, J = 1.98 Hz, 1 H), 7.70 (d, J = 8.55Hz, 1 H), 7.59 (dd, J = 8.62, 2.06 Hz, 1 H), 3.53- 3.69 (m, 2 H),3.36-3.50 (m, 3 H), 2.16-2.30 (m, 1 H), ES+ 350.92 2.01-2.13 (m, 1 H) 23

N-(1H- benzo[d]imidazol-2- yl)-1-cyanopyrrolidine- 3-carboxamide934-32-7 12.12 (br s, 1 H), 11.76 (br s, 1 H), 7.35-7.51 (m, 2 H),7.06-7.11 (m, 2 H), 3.56- 3.67 (m, 2 H), 3.41-3.52 (m, 2 H), 3.30-3.34(m, 1H), 2.17- 2.26 (m, 1 H), 2.06-2.16 ES+ 255.95 (m, 1 H) 24

1-cyano-N-(pyridin-2- yl)pyrrolidine-3- carboxamide 504-29-0 10.71 (s, 1H), 8.31-8.36 (m, 1 H), 8.08 (d, J = 8.24 Hz, 1 H), 7.79 (td, J = 7.86,1.98 Hz, 1 H), 7.12 (ddd, J = 7.33, 4.88, 0.92 Hz, 1 H), 3.57-3.64 (m,ES+ 216.98 1 H), 3.38-3.53 (m, 3 H), 3.29- 3.34 (m, 1 H), 2.12-2.22 (m,1 H), 1.99-2.10 (m, 1 H) 25

N-(5-chloropyridin-2- yl)-1-cyanopyrrolidine- 3-carboxamide 1072-98-610.89 (s, 1 H), 8.38-8.41 (m, 1 H), 8.12 (d, J = 8.85 Hz, 1 H), 7.92(dd, J = 8.85, 2.78 Hz, 1 H), 3.58-3.64 (m, 1 H), 3.33-3.54 (m, 4 H),2.12-2.22 ES+ 251.23 (m, 1 H), 2.00-2.10 (m, 1 H) 26

1-cyano-N-(5- methylpyridin-2- yl)pyrrolidine-3- carboxamide 1603-41-410.61 (s, 1 H), 8.16 (dd, J = 1.52, 0.92 Hz, 1 H), 7.98 (d, J = 8.55 Hz,1 H), 7.61 (dd, J = 8.55, 2.14 Hz, 1 H), 3.57-3.63 (m, 1 H), 3.43-3.52ES+ 231.03 (m, 2 H), 3.37-3.43 (m, 1 H), 3.26-3.33 (m, 1 H), 2.24 (s,3H), 2.10-2.20 (m, 1 H), 1.97-2.09 (m, 1 H) 27

1-cyano-N-(5- methoxypyridin-2- yl)pyrrolidine-3- carboxamide 10167-97-210.57 (s, 1 H), 8.00-8.06 (m, 2 H), 7.44 (dd, J = 9.16, 3.05 Hz, 1 H),3.81 (s, 3 H), 3.57- 3.63 (m, 1 H), 3.43-3.51 (m, 2 H), 3.37-3.43 (m, 1H), ES+ 247.23 3.26-3.32 (m, 1 H), 2.11- 2.20 (m, 1 H), 1.98-2.08 (m, 1H) 28

1-cyano-N-(5- morpholinopyridin-2- yl)pyrrolidine-3- carboxamide571189-78-1 10.50 (s, 1 H), 8.02 (d, J = 2.78 Hz, 1 H), 7.95 (d, J =9.16 Hz, 1 H), 7.42 (dd, J = 9.16, 3.05 Hz, 1 H), 3.71-3.78 (m, 4 H),3.56-3.63 (m, 1 H), 3.43- 3.50 (m, 2 H), 3.37-3.43 (m, 1 H), 3.24-3.31(m, 1 H), 3.07- 3.14 (m, 4 H), 2.10-2.20 ES+ 301.93 (m, 1 H), 1.98-2.07(m, 1 H) 29

1-cyano-N-(5- (piperidin-1- yl)pyridin-2- yl)pyrrolidine-3- carboxamide94924-94-4 10.45 (s, 1 H), 7.99 (d, J = 2.78 Hz, 1 H), 7.92 (d, J = 9.16Hz, 1 H), 7.39 (dd, J = 9.16, 3.05 Hz, 1 H), 3.56-3.63 (m, 1 H),3.36-3.51 (m, 3 H), 3.23-2.30 (m, 1 H), 3.06-3.16 (m, 4 H), 2.10-2.18(m, 1 H), 1.97-2.06 (m, 1 H), 1.57-1.67 ES+ 299.96 (m, 4 H), 1.48-1.56(m, 2 H) 30

N-(5-(1H- imidazol-1- yl)pyridin-2- cyanopyrrolidine-3- carboxamide935547-73-2 10.94 (s, 1 H), 8.70 (dd, J = 2.75, 0.61 Hz, 1 H), 8.29 (s,1 H), 8.18-8.25 (m, 1 H), 8.11-8.16 (m, 1 H), 7.80 (t, J = 1.22 Hz, 1H), 7.14 (s, 1 H), 3.59-3.66 (m, 1 H), 3.38- 3.55 (m, 4 H), 2.14-2.24(m, ES+ 282.93 1 H), 2.01-2.12 (m, 1 H) 31

1-cyano-N-(4- phenylpyridin-2- yl)pyrrolidine-3- carboxamide 60781-83-110.82 (s, 1 H), 8.36-8.47 (m, 2 H), 7.71-7.75 (m, 2 H), 7.40-7.58 (m,4H), 3.58- 3.67 (m, 1 H), 3.46-3.57 (m, 2 H), 3.36-3.47 (m, 2 H),2.15-2.19 (m, 1 H), 2.02- 2.13 (m, 1 H) ES+ 292.92 32

N-([2,3′-bipyridin]-6′- yl)-1- cyanopyrrolidine- 3-carboxamide31860-60-3 10.92 (s, 1 H), 9.06 (dd, J = 2.44, 0.61 Hz, 1 H), 8.66- 8.71(m, 1 H), 8.49 (dd, J = 8.85, 2.44 Hz, 1 H), 8.21 (d, J = 8.85 Hz, 1 H),8.01- 8.05 (m, 1 H), 7.91 (td, J = 7.78, 1.83 Hz, 1 H), 7.38 (ddd, J =7.48, 4.88, 1.07 Hz, ES+ 293.97 1 H), 3.60-3.66 (m, 1 H), 3.50-3.56 (m,1 H), 3.44-3.50 (m, 1 H), 3.34-3.44 (m, 2 H), 2.15-2.24 (m, 1 H),2.03-2.13 (m, 1 H) 33

N-([3,3′-bipyridin]-6- yl)-1- cyanopyrrolidine- 3-carboxamide 31970-30-610.88 (s, 1 H), 8.96 (d, J = 2.14 Hz, 1 H), 8.74 (t, J = 1.68 Hz, 1 H),8.60 (dd, J = 4.88, 1.53 Hz, 1 H), 8.21 (d, J = 1.53 Hz, 2 H), 8.13-8.18(m, 1 H), 7.51 (ddd, J = 7.94, 4.73, 0.76 Hz, 1 H), 3.60-3.66 (m, 1 H),3.38- 3.56 (m, 4 H), 2.15-2.24 ES+ 294.04 (m, 1 H), 2.03-2.12 (m, 1 H)34

N-([3,4′- bipyridin]-6-yl)-1- cyanopyrrolidine-3- carboxamide 79739-33-610.94 (s, 1 H), 8.84 (dd, J = 2.59, 0.76 Hz, 1 H), 8.64- 8.68 (m, 2 H),8.26-8.31 (m, 1 H), 8.20-8.25 (m, 1 H), 7.77-7.82 (m, 2 H), 3.60-3.66(m, 1 H), 3.50-3.56 (m, 1 H), 3.44-3.50 (m, 1 H), 3.35-3.44 (m, 2 H),2.17-2.23 (m, 1 H), ES+ 294.04 2.03-2.12 (m, 1 H) 35

1-cyano-N-(6- phenylpyridin-3- yl)pyrrolidine-3- carboxamide 126370-67-010.44 (br s, 1 H), 8.82 (s, 1 H), 7.94-8.17 (m, 4 H), 7.40- 7.47 (m, 3H), 3.41-3.69 (m, 4 H), 3.21-3.30 (m, 1 H), 2.15-2.27 (m, 1 H), 2.04-2.15 (m, 1 H) ES+ 292.99 36

1-cyano-N-(6- phenylpyridazin-3- yl)pyrrolidine-3- carboxamide14966-91-7 11.44 (s, 1 H), 8.40 (d, J = 9.46 Hz, 1 H), 8.26 (d, J = 9.46Hz, 1 H), 8.11 (dd, J = 8.0 Hz, 1.2 Hz, 2 H), 7.50-7.58 (m, 3 H),3.61-3.69 (m, 1 H), 3.53-3.59 (m, 1 H), 3.38-3.52 (m, 3 H), 2.17-2.27(m, 1 H), 2.05-2.16 ES+ 293.99 (m, 1 H) 37

1-cyano-N- (2- phenylpyrimidin-5- yl)pyrrolidine-3- carboxamide59808-52-5 10.63 (s, 1 H), 9.11 (s, 2 H), 8.31-8.39 (m, 2 H), 7.48- 7.56(m, 3 H), 3.61-3.68 (m, 1 H), 3.54-3.60 (m, 1 H), 3.41-3.52 (m, 2 H),3.24- 3.31 (m, 1 H), 2.17-2.27 (m, 1 H), 2.05-2.16 (m, 1 H) ES+ 293.9138

1-cyano-N-(5- cyclohexylpyridin-2- yl)pyrrolidine-3- carboxamideIntermediate 6 10.62 (s, 1 H), 8.19 (d, J = 2.44 Hz, 1 H), 7.99 (d, J =8.55 Hz, 1 H), 7.65 (dd, J = 8.55, 2.44 Hz, 1 H), 3.57-3.63 (m, 1 H),3.43-3.51 (m, 2 H), 3.26- 3.42 (m, 3 H), 2.11-2.21 (m, 1 H), 1.97-2.08(m, 1 H), 1.73-1.82 (m, 4 H), 1.68- ES+ 299.04 1.72 (m, 1 H), 1.29-1.47(m, 4 H), 1.17-1.29 (m, 1 H) 39

N-(1-benzyl-1H- indazol-5-yl)-1- cyanopyrrolidine-3- carboxamide23856-21-5 10.14 (s, 1 H), 8.14 (d, J = 1.22 Hz, 1 H), 8.07 (d, J = 0.92Hz, 1 H), 7.65 (d, J = 8.85 Hz, 1 H), 7.43 (dd, J = 9.16, 1.83 Hz, 1 H),7.24-7.33 (m, 3 H), 7.18- 7.22 (m, 2 H), 5.63 (s, 2 H), 3.59-3.66 (m, 1H), 3.47-3.55 (m, 2 H), 3.41-3.47 (m, 1 H), 3.18-3.21 (m, 1 H),2.13-2.22 (m, 1 H), 2.03-2.11 (m, 1 H) ES+ 346.18 40

1-cyano-N-(1-propyl- 1H-benzo[d]imidazol- 5-yl)pyrrolidine-3-carboxamide 177843-27-5 10.08 (s, 1 H), 8.19 (s, 1 H), 7.98 (d, J = 1.83Hz, 1 H), 7.54 (d, J = 8.85 Hz, 1 H), 7.39 (dd, J = 8.85, 1.83 Hz, 1 H),4.18 (t, J = 7.02 Hz, 2 H), 3.60-3.66 (m, 1 H), 3.41-3.55 (m, 3 H),3.16-3.34 (m, 1 H), 2.14-2.23 (m, 1 H), 2.02-2.13 (m, 1 H), ES+ 298.231.75-1.82 (m, 2 H), 0.83 (t, J = 7.48 Hz, 3 H)

Compounds in Table 2 were synthesised using a procedure similar to thatdescribed for Example 1 using(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid.

TABLE 2 Amine ¹H NMR Ex R1 Name CAS Number (400 MHz, DMSO-d₆) δ ppm MS41

(S)-1-cyano- N-(1-phenyl- 1H-imidazol- 4- yl)pyrrolidine- 3- carboxamide158688-63-2 10.75 (s, 1 H), 8.14 (d, J = 1.83 Hz, 1 H), 7.72 (d, J =1.53 Hz, 1 H), 7.62-7.64 (m, 2 H), 7.50- 7.53 (m, 2 H), 7.30-7.40 (m, 1H), 3.55-3.65 (m, 1 H), 3.25-3.37 (m, 4 H), 2.08- 2.19 (m, 1 H),1.95-2.08 (m, 1 H) ES+ 282.33 42

(S)-1-cyano- N-(5-phenyl- 1H-pyrazol- 3- yl)pyrrolidine- 3- carboxamide1572-10-7 12.90 (s, 1 H), 10.70 (s, 1 H), 7.71-7.72 (m, 2 H), 7.43- 7.45(m, 2 H), 7.29-7.38 (m, 1 H), 6.93 (d, J = 1.83 Hz, 1 H), 3.58-3.62 (m,1 H), 3.37- 3.54 (m, 3 H), 3.21-3.25 (m, 1 H), 2.13-2.17 (m, 1 H), 2.01-2.06 (m, 1 H) ES+ 282.28 43

(S)-1-cyano- N-(5- (tetrahydro- 2H-pyran-4- yl)-1H- pyrazol-3-yl)pyrrolidine- 3- carboxamide 1000896-69- 4 12.13 (s, 1 H), 10.52 (s, 1H), 6.32 (s, 1 H), 3.87-3.90 (m, 2 H), 3.56-3.59 (m, 1 H), 3.37- 3.48(m, 5 H), 3.16-3.20 (m, 1 H), 2.81-2.87 (m, 1 H), 2.02-2.12 (m, 1 H),1.98- 2.00 (m, 1 H), 1.78-1.81 (m, 2 H), 1.53-1.64 (m, 2 H) ES+ 290.1 44

(S)-1-cyano- N-(1-phenyl- 1H-1,2,3- triazol-4- yl)pyrrolidine- 3-carboxamide 2076-64-4 11.33 (s, 1 H), 8.77 (s, 1 H), 7.89-8.00 (m, 2 H),7.55- 7.64 (m, 2 H), 7.42-7.53 (m, 1 H), 3.59-3.70 (m, 1 H), 3.38-3.57(m, 3 H), 3.25- 3.34 (m, 1 H), 2.12-2.25 (m, 1 H), 1.98-2.10 (m, 1 H)ES+ 283.28 45

(S)-1-cyano- N-(1-phenyl- 1H-pyrazol- 3- yl)pyrrolidine- 3- carboxamide1128-56-9 10.96 (s, 1 H), 8.43 (d, J = 2.74 Hz, 1 H), 7.76-7.78 (m, 2H), 7.47-7.51 (m, 2 H), 7.25- 7.31 (m, 1 H), 6.81 (d, J = 2.44 Hz, 1 H),3.59-3.64 (m, 1 H), 3.49-3.53 (m, 1 H), 3.37- 3.47 (m, 2 H), 3.21-3.30(m, 1 H), 2.12-2.21 (m, 1 H), 2.00-2.10 (m, 1 H) ES+ 282.08 46

(S)-1-cyano- N-(4- methylbenzo [d]thiazol-2- yl)pyrrolidine- 3-carboxamide 1477-42-5 12.67 (s, 1 H), 7.80 (d, J = 7.63 Hz, 1 H),7.25-7.29 (m, 1 H), 7.19-7.25 (m, 1 H), 3.62- 3.68 (m, 1 H), 3.55-3.61(m, 1 H), 3.42-3.52 (m, 2 H), 3.36-3.42 (m, 1 H), 2.58 (s, 3 H),2.18-2.28 (m, 1 H), 2.05- 2.16 (m, 1 H) ES+ 286.94 47

(S)-1-cyano- N-(7- methylbenzo [d]thiazol-2- yl)- pyrrolidine- 3-carboxamide 14779-18-1 12.58 (br s, 1 H), 7.61 (d, J = 7.02 Hz, 1 H),7.38 (t, J = 6.40 Hz, 1 H), 7.16 (d, J = 7.01 Hz, 1 H), 3.63-3.67 (m, 1H), 3.57-3.60 (m, 1 H), 3.43-3.47 (m, 2 H), 3.38- 3.42 (m, 1 H), 2.52(s, 3 H), 2.21-2.23 (m, 1 H), 2.08- 2.13 (m, 1 H) ES+ 287.33 48

(S)-N-(4- bromobenzo [d]thiazol-2- yl)-1-cyano- pyrrolidine- 3-carboxamide 20358-02-5 12.96 (br s, 1 H), 8.00 (d, J = 7.32 Hz, 1 H),7.67 (d, J = 7.63 Hz, 1 H), 7.22 (t, J = 7.78 Hz, 1 H), 3.57-3.67 (m, 2H), 3.42-3.49 (m, 2 H), 3.37-3.41 (m, 1 H), 2.18- 2.27 (m, 1 H),2.08-2.17 (m, 1 H) ES+ 352.87 49

(S)-1-cyano- N- (imidazo[1,2- a]pyridin-2- yl)- pyrrolidine- 3-carboxamide 39588-26-6 10.92 (br s, 1 H), 8.54 (d, J = 7.02 Hz, 1 H),8.11 (s, 1 H), 7.42 (d, J = 9.16 Hz, 1 H), 7.22 (t, J = 6.87 Hz, 1 H),6.87 (t, J = 6.87 Hz, 1 H), 3.59-3.66 (m, 1 H), 3.45-3.55 (m, 2 H),3.36-3.42 (m, 1 H), 3.22- 3.32 (m, 1 H), 2.12-2.23 (m, 1 H), 2.01-2.11(m, 1 H) ES+ 256.00 50

(S)-N-(7- bromoimidazo [1,2- a]pyridin-2- yl)-1- cyanopyrroli- dine-3-carboxamide 865604-33-7, preparation described in WO2005089763 11.01 (s,1 H), 8.52 (d, J = 7.02 Hz, 1 H), 8.16 (s, 1 H), 7.75 (d, J = 1.83 Hz, 1H), 7.06 (dd, J = 7.17, 1.98 Hz, 1 H), 3.58- 3.65 (m, 1 H), 3.37-3.52(m, 3 H), 3.25-3.32 (m, 1 H), 2.13-2.19 (m, 1 H), 2.01- 2.08 (m, 1 H)ES+ 334.0, 336.0 51

(S)-N-(6- bromoimidazo [1,2- a]pyridin-2- yl)-1- cyanopyrroli- dine-3-carboxamide 947248-52-4, preparation described in WO2012174312 11.01 (s,1 H), 8.91 (d, J = 1.22 Hz, 1 H), 8.13 (s, 1 H), 7.40- 7.44 (m, 1 H)7.31-7.36 (m, 1 H), 3.59-3.64 (m, 1 H), 3.36-3.53 (m, 3 H), 3.25- 3.32(m, 1 H), 2.12-2.22 (m, 1 H), 2.01-2.09 (m, 1 H) ES+ 333.9, 335.9 52

(S)-1-cyano- N- (pyrazolo[1,5- a]pyridin-2- yl)pyrrolidine- 3-carboxamide 51119-05-2, preparation described in WO2012102297 11.00 (s,1 H), 8.51 (dd, J = 6.80, 0.80 Hz, 1 H), 7.58 (d, J = 8.85 Hz, 1 H),7.19 (t, J = 6.80 Hz, 1 H), 6.85 (s, 1 H), 6.79-6.83 (m, 1 H), 3.60-3.65 (m, 1 H), 3.49-3.53 (m, 1 H), 3.45-3.47 (m, 1 H), 3.42-3.46 (m, 1H), 3.26- 3.33 (m, 1 H), 2.13-2.22 (m, 1 H), 2.01-2.07 (m, 1 H) ES+256.63 53

(S)-1-cyano- N-(4- methoxypyridin- 2- yl)pyrrolidine- 3- carboxamide10201-73-7 10.68 (s, 1 H), 8.13 (d, J = 5.79 Hz, 1 H), 7.73 (s, 1 H),6.73 (dd, J = 5.79, 2.44 Hz, 1 H), 3.82 (s, 3 H), 3.57-3.63 (m, 1 H),3.47-3.52 (m, 1 H), 3.38- 3.50 (m, 2 H), 3.30-3.37 (m, 1 H), 2.11-2.21(m, 1 H), 1.99-2.08 (m, 1 H) ES+ 247.06 54

(S)-1-cyano- N-(5- phenylpyridin- 2- yl)pyrrolidine- 3- carboxamide33421-40-8 10.84 (s, 1 H), 8.67 (d, J = 1.83 Hz, 1 H), 8.09-8.22 (m, 2H), 7.72 (d, J = 7.32 Hz, 2 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.40 (t, J =7.6 Hz, 1 H), 3.59-3.65 (m, 1 H), 3.34-3.54 (m, 4 H), 2.14-2.26 (m, 1H), 2.02- 2.13 (m, 1 H) ES+ 293.23 55

(S)-1-cyano- N-(6- phenylpyridin- 2- yl)pyrrolidine- 3- carboxamide39774-25-9 10.74 (s, 1 H), 8.03-8.12 (m, 3 H), 7.89 (t, J = 7.93 Hz, 1H), 7.69 (d, J = 7.63 Hz, 1 H), 7.43- 7.52 (m, 3 H), 3.61-3.65 (m, 1 H),3.46-3.56 (m, 3 H), 3.37-3.44 (m, 1 H), 2.15- 2.25 (m, 1 H), 2.03-2.13(m, 1 H) ES+ 292.99 56

(S)-1-cyano- N-(1,8- naphthyridin- 2- yl)pyrrolidine- 3- carboxamide15992-83-3 11.36 (s, 1 H), 9.01 (dd, J = 4.42, 1.98 Hz, 1 H), 8.45- 8.49(m, 1 H), 8.39-8.44 (m, 2 H), 7.52-7.56 (m, 1 H), 3.62-3.68 (m, 1 H),3.54- 3.59 (m, 1 H), 3.42-3.53 (m, 3 H), 2.18-2.27 (m, 1 H), 2.04-2.18(m, 1 H) ES+ 268.28 57

(S)-N-(5- benzylthiazol- 2-yl)-1- cyanopyrroli- dine-3- carboxamide121952-97-4 12.18 (s, 1 H), 7.29-7.35 (m, 2 H), 7.20-7.29 (m, 4 H), 4.08(s, 2 H), 3.55-3.62 (m, 1 H), 3.46-3.50 (m, 1 H), 3.34- 3.43 (m, 2 H),3.25-3.29 (m, 1 H), 2.10-2.21 (m, 1 H), 1.98-2.06 (m, 1 H) ES+ 313.28 58

(S)-1-cyano- N- (isoquinolin- 3- yl)pyrrolidine- 3- carboxamide25475-67-6 10.85 (s, 1 H), 9.16 (s, 1 H), 8.50 (s, 1 H), 8.06 (d, J =7.6 Hz, 1 H), 7.91 (d, J = 7.93 Hz, 1 H), 7.72 (ddd, J = 8.24, 6.86,1.06 Hz, 1 H), 7.54 (ddd, J = 8.16, 6.94, 1.06 Hz, 1 H), 3.62-3.67 (m, 1H), 3.47- 3.57 (m, 2 H), 3.38-3.46 (m, 2 H), 2.16-2.24 (m, 1H),2.05-2.13 (m, 1 H) ES+ 267.10 59

(S)-1-cyano- N-(5- (tetrahydro- 2H-pyran-4- yl)thiazol-2-yl)pyrrolidine- 3- carboxamide Intermediate 3 12.18 (s, 1 H), 7.22 (s, 1H), 3.88-3.91 (m, 2 H), 3.58- 3.63 (m, 1 H), 3.48-3.53 (m, 1 H),3.39-3.45 (m, 3 H), 3.28-3.33 (m, 1 H), 3.01- 3.07 (m, 2H), 2.15-2.19(m, 1 H), 2.01-2.06 (m, 1 H), 1.83-1.87 (m, 2 H), 1.56- 1.66 (m, 2 H)ES+ 307.47 60

(S)-1-cyano- N-(1-methyl- 5-phenyl-1H- pyrazol-3- yl)pyrrolidine- 3-carboxamide Intermediate 4 10.70 (s, 1 H), 7.46-7.51 (m, 5 H), 6.61 (s,1 H), 3.76 (s, 3 H), 3.57-3.61 (m, 1 H), 3.35- 3.40 (m, 2H), 3.42-3.49(m, 1 H), 3.17-3.24 (m, 1 H), 2.10-2.18 (m, 1H), 1.97- 2.06 (m, 1 H) ES+296.33 61

(S)-1-cyano- N-(5-(4- methoxy- piperidin-1- yl)pyridin-2-yl)pyrrolidine- 3- carboxamide Intermediate 5 10.45 (s, 1 H), 8.02 (d, J= 2.78 Hz, 1 H), 7.92 (d, J = 9.16 Hz, 1 H), 7.41 (dd, J = 9.16, 3.05Hz, 1 H), 3.56-3.62 (m, 1 H), 3.37-3.50 (m, 6 H), 3.25- 3.30 (m, 4 H),2.84-2.93 (m, 2 H), 2.10-2.19 (m, 1 H), 1.99-2.07 (m, 1 H), 1.91- 1.94(m, 2 H), 1.46-1.58 (m, 2 H) ES+ 330.06 62

(S)-N-(6-(1H- 1,2,3-triazol- 1- yl)benzo[d] thiazol-2-yl)-1-cyanopyrroli- dine-3- carboxamide Intermediate 7 12.76 (s, 1 H), 8.86(s, 1 H), 8.60 (s, 1 H), 7.93-8.01 (m, 3 H), 3.58-3.69 (m, 2 H), 3.40-3.52 (m, 3 H), 2.22-2.27 (m, 1 H), 2.10-2.16 (m, 1 H) ES+ 340.23 63

(S)-N-(6-(2H- 1,2,3-triazol- 2- yl)benzo[d] thiazol-2-yl)-1-cyanopyrroli- dine-3- carboxamide Intermediate 8 12.71 (s, 1 H), 8.69(d, J = 1.83 Hz, 1 H), 8.13-8.15 (m, 2 H), 8.12 (dd, J = 8.80, 2.00 Hz,1 H), 7.91 (d, J = 8.85 Hz, 1 H), 3.57-3.69 (m, 2 H), 3.39- 3.51 (m, 3H), 2.21-2.28 (m, 1 H), 2.07-2.17 (m, 1 H) ES+ 340.28 64

(S)-1-cyano- N-(5-(4- (methylcarba- moyl)phenyl) thiazol-2-yl)pyrrolidine- 3- carboxamide Intermediate 9 12.49 (s, 1H), 8.49 (d, J= 4.4 Hz, 1H), 8.03 (s, 1 H), 7.87 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4Hz, 2H), 3.62-3.66 (m, 1 H), 3.54-3.58 (m, 1 H), 3.43-3.48 (m, 2H),3.37- 3.40 (m, 1 H), 2.79 (d, H = 4.4 Hz, 3 H), 2.19-2.23 (m, 1 H),2.06-2.11 (m, 1 H) ES+ 354.38 65

(S)-1-cyano- N-(4-methyl- 5- (morpholino- methyl)thiazol- 2-yl)pyrrolidine- 3- carboxamide Intermediate 13 12.14 (br s, 1 H),3.46-3.54 (m, 7 H), 3.44-3.48 (m, 1 H), 3.37-3.43 (m, 2 H), 3.25- 3.29(m, 1 H), 2.37-2.42 (m, 4 H), 2.20 (s, 3 H), 2.14-2.18 (m, 1 H),2.01-2.06 (m, 1 H) ES+ 336.04

Example 66(S)-1-cyano-N-(5-(4-fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 2)

Step a.

To a solution of 2-aminothiazole (35 mmol) in THF (35 ml) was added TEA(52 mmol) at rt. The resulting reaction mixture cooled to 0° C. Aceticanhydride (52 mmol) was added to the reaction mixture. The reactionmixture was stirred at rt for 2 h. Precipitation of solids was observedin the reaction mixture. The obtained precipitates were filtered offunder reduced pressure, washed with ice water (2×20 ml), dried undervacuum yielding N-(thiazol-2-yl)acetamide (16.9 mmol). This material wasused directly for the next step without further purification. MS: ES+143.19; H NMR (400 MHz, DMSO-d₆) δ ppm 12.09 (br s, 1H), 7.45 (d, J=3.60Hz, 1H), 7.18 (d, J=3.60 Hz, 1H), 2.14 (s, 3H).

Step b.

A solution of N-(thiazol-2-yl)acetamide (7.9 mmol) and1-bromo-4-fluorobenzene (11.8 mmol) in DMF (10 ml) was stirred at rtunder nitrogen atmosphere in a microwave glass tube for 5 min. K₃PO₄(9.4 mmol) was added to the reaction mixture at rt under nitrogenatmosphere. The reaction mixture was purged with nitrogen for 30 min.Pd(OAc)₂ (0.5 mmol) and tricyclohexylphosphine (0.4 mmol) were added tothe reaction mixture at rt under nitrogen atmosphere and the glass tubewas sealed. The sealed tube was subjected to microwave irradiation at140° C. for 1.5 h. The resulting reaction mixture was poured into water(30 ml) and extracted with EtOAc (3×30 ml). The combined organic phasewas collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography (70-80% EtOAc in hexane) yieldingN-(5-(4-fluorophenyl)thiazol-2-yl)acetamide (1.3 mmol). MS: ES+ 237.28;¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.19 (s, 1H), 7.83 (s, 1H), 7.64-7.67(m, 2H), 7.23-7.28 (m, 2H), 2.16 (s, 3H).

Step c.

To a solution of N-(5-(4-fluorophenyl) thiazol-2-yl)acetamide (1.3 mmol)in 1,4-dioxane (6 ml) was added concentrated HCl (24 ml) at rt. Thereaction mixture was heated at 100° C. for 4 h. The resulting reactionmixture was poured into water (30 ml) and basified with aqueous 1M NaOHsolution. The obtained precipitates were filtered off under reducedpressure, washed with ice water (3×10 ml) and dried under vacuumyielding 5-(4-fluorophenyl)thiazol-2-amine (0.7 mmol). This material wasused directly for the next step without further purification. MS: ES+195.18; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.43-7.46 (m, 2H), 7.35 (s, 1H),7.17-7.29 (m, 2H), 7.15 (br s, 2H).

Steps d-f.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 1 using(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid. MS: ES+316.91; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.43 (br s, 1H), 7.87 (s, 1H),7.64-7.68 (m, 2H), 7.25-7.29 (m, 2H), 3.61-3.65 (m, 1H), 3.53-3.57 (m,1H), 3.40-3.50 (m, 3H), 2.16-2.33 (m, 1H), 2.03-2.12 (m, 1H).

Example 67(S)-1-cyano-N-(5-(3,4-difluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 66using 1-bromo-3,4-difluorobenzene. MS: ES+ 334.99; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 7.95 (s, 1H), 7.77-7.82 (m, 1H), 7.43-7.52(m, 2H), 3.61-3.65 (m, 1H), 3.53-3.57 (m, 1H), 3.37-3.50 (m, 2H),3.25-3.29 (m, 1H), 2.16-2.25 (m, 1H), 2.04-2.12 (m, 1H).

Example 68(S)-1-cyano-N-(5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 66using 1-bromo-4-(trifluoromethyl)benzene. MS: ES+ 366.87; ¹H NMR (400MHz, DMSO-d6) δ ppm 12.55 (br s, 1H), 8.08-8.16 (m, 1H), 7.82-7.90 (m,2H), 7.74-7.80 (m, 2H), 3.61-3.65 (m, 1H), 3.57-3.58 (m, 1H), 3.33-3.47(m, 3H), 2.16-2.30 (m, 1H), 2.04-2.15 (m, 1H).

Example 69(S)-1-cyano-N-(5-(pyridin-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 66using 4-bromopyridine hydrochloride. MS: ES+ 300.07; ¹H NMR (400 MHz,DMSO-d6) δ ppm 12.68 (s, 1H), 8.61 (d, J=6.0 Hz, 2H), 8.32 (s, 1H), 7.74(d, J=6.0 Hz, 2H), 3.59-3.66 (m, 1H), 3.55-3.57 (m, 1H), 3.43-3.50 (m,2H), 3.34-3.41 (m, 1H), 2.19-2.24 (m, 1H), 2.07-2.12 (m, 1H).

Example 70 (S)-1-cyano-N-(5-(pyridin-2-yl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 66using 2-bromopyridine. MS: ES+ 300.05; ¹H NMR (400 MHz, DMSO-d6) δ ppm12.42 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 8.19 (s, 1H), 7.91-7.95 (m, 1H),7.80-7.84 (m, 1H), 7.24-7.27 (m, 1H), 3.62-3.66 (m, 1H), 3.54-3.58 (m,1H), 3.40-3.51 (m, 3H), 2.17-2.28 (m, 1H), 2.04-2.13 (m, 1H).

Example 71 (R)-1-cyano-N-(5-phenylpyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid and2-amino-5-phenylpyridine. MS: ES+ 292.99; ¹H NMR (400 MHz, DMSO-d₆) δppm 10.83 (s, 1H), 8.67 (d, J=1.67 Hz, 1H), 8.10-8.20 (m, 2H), 7.70-7.75(m, 2H), 7.49 (t, J=7.6 Hz, 2H), 7.39 (t, J=7.6 Hz, 1H), 3.59-3.67 (m,1H), 3.32-3.55 (m, 4H), 2.14-2.24 (m, 1H), 2.02-2.12 (m, 1H).

Example 72(2S,3S)-1-cyano-2-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 1 and 2-amino-5-phenylthiazole. Purification bypreparative HPLC; mobile phase: (A) 100% n-hexane (B) 100% IPA, column:YMC PACKSIL, 250×20 mm, 5 μm, flow rate: 18 ml/min. MS: ES+ 312.90; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.41 (br s, 1H), 7.90 (s, 1H), 7.60-7.63(m, 2H), 7.39-7.45 (m, 2H), 7.27-7.34 (m, 1H), 3.96-4.04 (m, 1H),3.60-3.68 (m, 1H), 3.40-3.46 (m, 1H), 3.28-3.34 (m, 1H), 2.17-2.24 (m,1H), 2.03-2.10 (m, 1H), 1.10 (d, J=6.41 Hz, 3H).

Example 73(2S,3S)-1-cyano-N-(5-(4-fluorophenyl)thiazol-2-yl)-2-methylpyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 66using Intermediate 1. MS: ES+ 331.05; ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.42 (s, 1H), 7.87 (s, 1H), 7.65-7.69 (m, 2H), 7.25-7.29 (m, 2H),3.98-4.02 (m, 1H), 3.61-3.66 (m, 1H), 3.40-3.46 (m, 1H), 3.28-3.32 (m,1H), 2.16-2.23 (m, 1H), 2.06-2.09 (m, 1H), 1.10 (d, J=6.71 Hz, 3H).

Example 74(2S,3S)-1-cyano-2-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 1 and 4-amino-1-phenylimidazole. Purification bypreparative HPLC; mobile phase: (A) 100% n-hexane (B) 100% IPA, column:YMC PACKSIL, 250×20 mm, 5 μm, flow rate: 20 ml/min. MS: ES+ 296.09; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.69 (s, 1H), 8.14 (d, J=1.83 Hz, 1H),7.73 (d, J=1.83 Hz, 1H), 7.62-7.66 (m, 2H), 7.50-7.54 (m, 2H), 7.33-7.39(m, 1H), 3.90-3.98 (m, 1H), 3.59-3.68 (m, 1H), 3.34-3.43 (m, 1H),3.18-3.23 (m, 1H), 2.09-2.21 (m, 1H), 1.95-2.05 (m, 1H), 1.11 (d, J=6.71Hz, 3H).

Example 75(2S,3S)-1-cyano-2-methyl-N-(5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 1 and 5-amino-3-phenylpyrazole. Purification bypreparative HPLC; mobile phase: (A) 100% n-hexane (B) 100% IPA, column.YMC PACKSIL, 250×20 mm, 5 μm, flow rate. 20 ml/min. MS: ES+ 296.47; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.89 (br s, 1H), 10.64 (br s, 1H),7.70-7.74 (m, 2H), 7.41-7.47 (m, 2H), 7.31-7.37 (m, 1H), 6.94 (br s,1H), 3.93-3.98 (m, 1H), 3.59-3.67 (m, 1H), 3.38-3.44 (m, 1H), 3.16-3.21(m, 1H), 2.12-2.20 (m, 1H), 1.97-2.04 (m, 1H), 1.13 (d, J=6.40 Hz, 3H).

Example 76 (2S,3S)-1-cyano-2-methyl-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 1 and Intermediate 3. MS: ES+ 321.18; ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.19 (br s, 1H), 7.19 (s, 1H), 3.93-3.98 (m, 1H),3.86-3.92 (m, 2H), 3.58-3.64 (m, 1H), 3.34-3.44 (m, 3H), 3.17-3.27 (m,1H), 2.99-3.05 (m, 1H), 2.12-2.19 (m, 1H), 1.99-2.06 (m, 1H), 1.83-1.86(m, 2H), 1.56-1.86 (m, 2H), 1.05 (d, J=6.4 Hz, 3H).

Example 77(2S,3S)—N-(5-(2-chlorophenyl)thiazol-2-yl)-1-cyano-2-methylpyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 1 and 5-(2-chlorophenyl)thiazol-2-amine. MS: ES+347.63; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.43 (br s, 1H), 7.28 (s, 1H),7.67 (dd, J=7.2 Hz, 1.6 Hz, 1H), 7.59 (dd, J=8.0 Hz, 2.0 Hz, 1H),7.37-7.44 (m, 2H), 3.97-4.03 (m, 1H), 3.61-3.66 (m, 1H), 3.40-3.46 (m,1H), 3.29-3.32 (m, 1H), 2.16-2.24 (m, 1H), 2.02-2.09 (m, 1H), 1.10 (d,J=6.4 Hz, 3H).

Example 781-cyano-3-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using 1-(tert-butoxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid and2-amino-5-phenylthiazole. MS: ES+ 312.9; ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.30 (s, 1H), 7.93 (s, 1H), 7.61-7.63 (m, 2H), 7.44-7.40 (m, 2H),7.29-7.33 (m, 1H), 3.86-3.89 (m, 1H), 3.48-3.52 (m, 1H), 3.37-3.41 (m,1H), 3.29-3.33 (m, 1H), 2.38-2.45 (m, 1H), 1.92-1.99 (m, 1H), 1.42 (s,3H).

Example 79l-cyano-3-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using 1-(tert-butoxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid and4-bmino-1-phenylimidazole. MS: ES+ 296.53; ¹H NMR (400 MHz, DMSO-d₆) δppm 10.52 (s, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H),7.63-7.65 (m, 2H), 7.50-7.54 (m, 2H), 7.34-7.38 (m, 1H), 3.85 (d, J=9.16Hz, 1H), 3.36-3.60 (m, 2H), 3.25 (d, J=9.16 Hz, 1H), 2.37-2.42 (m, 1H),1.89-1.94 (m, 1H), 1.38 (s, 3H).

Example 801-cyano-3-(methoxymethyl)-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 1)

Step a.

To a solution of Intermediate 11 (1.0 mmol) in DMF (5 ml) was added HATU(1.5 mmol) and 5-phenylthiazol-2-amine (1.0 mmol) at rt. The reactionmixture was stirred for 10 min. TEA (2.9 mmol) was added dropwise to thereaction mixture. The reaction mixture was stirred at rt for 6 h. Theresulting reaction mixture was poured into water (20 ml) and extractedwith EtOAc (3×20 ml). The combined organic phase was collected, driedover Na₂SO₄, filtered and concentrated under reduced pressure yieldingtert-butyl3-(methoxymethyl)-3-((5-phenylthiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.5 mmol). This material was directly used for the next step withoutfurther purification. MS: ES+ 418.48

Steps b-c.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 1 according to Scheme 1steps b and c. MS: ES+ 343.33; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.54 (brs, 1H), 7.87 (s, 1H), 7.59-7.61 (m, 2H), 7.39-7.43 (m, 2H), 7.27-7.30(m, 1H), 3.92 (d, J=9.60 Hz, 1H), 3.80 (d, J=9.60 Hz, 1H), 3.62 (d,J=9.60 Hz, 1H), 3.45-3.52 (m, 1H), 3.32-3.41 (m, 2H), 3.25 (s, 3H),2.30-2.36 (m, 1H), 1.98-2.06 (m, 1H).

Example 81 1,3-dicyano-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using 2-amino-5-methylthiazole and Intermediate 12. MS: ES+ 324.48; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 13.49 (s, 1H), 7.96 (s, 1H), 7.61-7.63 (m,2H), 7.40-7.44 (m, 2H), 7.31-7.33 (m, 1H), 3.93-4.00 (m, 2H), 3.59-3.63(m, 2H), 2.57-2.67 (m, 2H).

Example 82(3S,4S)-1-cyano-4-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 2 and 2-amino-5-phenylthiazole. Purification bypreparative chiral HPLC; mobile phase: (A) 70-50% n-hexane (B) 30-50%IPA, column: Chiralpak IC, 250×10 mm, 5 μm, flow rate: 8 ml/min. MS: ES+313.23; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.48 (br s, 1H), 7.91 (s, 1H),7.61-7.63 (m, 2H), 7.39-7.44 (m, 2H), 7.29-7.35 (m, 1H), 3.73-3.77 (m,1H), 3.59-3.63 (m, 1H), 3.52-3.56 (m, 1H), 3.05-3.10 (m, 1H), 2.94-2.99(m, 1H), 2.46-2.47 (m, 1H), 1.06 (d, J=6.71 Hz, 3H).

Example 83(3S,4S)-1-cyano-4-methyl-N-(5-methylthiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 2 and 2-amino-5-methylthiazole. Purification bypreparative chiral HPLC; mobile phase: (A) 70-50% n-hexane (B) 30-50%IPA, column: Chiralpak IC, 250×10 mm, 5 m, flow rate: 8 ml/min. MS: ES+251.17; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.20 (s, 1H), 7.16 (d, J=1.2Hz, 1H), 3.69-3.74 (m, 1H), 3.57-3.61 (m, 1H), 3.47-3.52 (m, 1H),3.03-3.07 (m, 1H), 2.87-2.95 (m, 1H), 2.40-2.48 (m, 1H), 2.35 (s, 3H),1.03 (d, J=6.71 Hz, 3H).

Example 84(±)-trans-N-(5-(2-chlorophenyl)thiazol-2-yl)-1-cyano-4-methylpyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 2 and Intermediate 10. MS: ES+ 347.07; ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.57 (s, 1H), 7.82 (s, 1H), 7.67 (dd, J=7.2, 1.6Hz, 1H), 7.59 (dd, J=7.6, 2.0 Hz, 1H), 7.37-7.45 (m, 2H), 3.73-3.77 (m,1H), 3.59-3.63 (m, 1H) 3.53-3.57 (m, 1H), 3.06-3.10 (m, 1H), 2.94-3.01(m, 1H), 2.46-2.49 (m, 1H), 1.06 (d, J=6.71 Hz, 3H).

Example 85(±)-1-cyano-4-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 2 and 4-amino-1-phenylimidazole. MS: ES+ 296.38; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.80 (s, 1H), 8.14 (d, J=1.52 Hz, 1H),7.74 (d, J=1.52 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.51 (t, J=7.6 Hz, 2H),7.33-7.39 (m, 1H), 3.67-3.72 (m, 1H), 3.60-3.64 (m, 1H), 3.45-3.50 (m,1H), 3.01-3.06 (m, 1H), 2.85-2.91 (m, 1H), 2.40-2.45 (m, 1H), 1.03 (d,J=6.71 Hz, 3H).

Example 86(±)-1-cyano-4-ethyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 17 and 2-amino-5-phenylthiazole. MS: ES+ 327.43; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.51 (s, 1H), 7.91 (s, 1H), 7.61-7.64 (m,2H), 7.40-7.45 (m, 2H), 7.30-7.34 (m, 1H) 3.72-3.76 (m, 1H), 3.62-3.66(m, 1H), 3.49-3.53 (m, 1H), 3.13-3.17 (m, 1H), 3.01-3.05 (m, 1H),2.38-2.41 (m, 1H), 1.46-1.51 (m, 1H), 1.36-1.42 (m, 1H), 0.87 (t, J=7.6Hz, 3H).

Example 87(±)-1-cyano-4-ethyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using Intermediate 17 and 1-phenyl-1H-imidazol-4-amine. MS: ES+ 310.13;¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.82 (s, 1H), 8.14 (d, J=1.6 Hz, 1H),7.74 (d, J=1.6 Hz, 1H), 7.62-7.74 (m, 2H), 7.49-7.53 (m, 2H), 7.34-7.39(m, 1H), 3.63-3.70 (m, 2H), 3.40-3.50 (m, 1H), 3.07-3.12 (m, 1H),2.91-2.97 (m, 1H), 2.30-2.35 (m, 1H), 1.44-1.49 (m, 1H), 1.29-1.38 (m,1H), 0.86 (d, J=7.6 Hz, 3H).

Example 881-cyano-5-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using 1-(tert-butoxycarbonyl)-5-methylpyrrolidine-3-carboxylic acid(prepared according to the method described in WO2010059658) and2-amino-5-phenylthiazole. The compound was a mixture of diastereomers86:14, the peaks mentioned in below NMR are just for the majordiastereomer. MS: ES+ 313.13; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.41 (s,1H), 7.90 (s, 1H), 7.61-7.63 (m, 2H), 7.40-7.44 (m, 2H), 7.29-7.33 (m,1H), 3.61-3.72 (m, 3H), 3.33-3.42 (m, 1H), 2.34-2.43 (m, 1H), 1.63-1.72(m, 1H), 1.27 (d, J=6.10 Hz, 3H).

Example 891-cyano-5-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using 1-(tert-butoxycarbonyl)-5-methylpyrrolidine-3-carboxylic acid(prepared according to the method described in WO2010059658) and4-amino-1-phenylimidazole. The compound was a mixture of diastereomers89:11, the peaks mentioned in below NMR are just for the majordiastereomer. MS: ES+ 296.10; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.73 (s,1H), 8.13 (d, J=1.52 Hz, 1H), 7.70 (d, J=1.52 Hz, 1H), 7.61-7.65 (m,2H), 7.48-7.54 (m, 2H), 7.33-7.39 (m, 1H), 3.54-3.71 (m, 3H), 3.23-3.33(m, 1H), 2.28-2.32 (m, 1H), 1.59-1.67 (m, 1H), 1.20-1.27 (m, 3H).

Example 901-cyano-5-methyl-N-(5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 1using 1-(tert-butoxycarbonyl)-5-methylpyrrolidine-3-carboxylic acid(prepared according to the method described in WO2010059658) and5-amino-3-phenylpyrazole. The compound was a mixture of diastereomers88:12, the peaks mentioned in below NMR are just for the majordiastereomer. MS: ES+ 296.08; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.89 (brs, 1H), 10.67 (s, 1H), 7.70-7.72 (m, 2H), 7.42-7.47 (m, 2H), 7.31-7.37(m, 1H), 6.88 (br s, 1H), 3.54-3.73 (m, 3H), 3.20-3.32 (m, 1H),2.29-2.37 (m, 1H), 1.60-1.68 (m, 1H), 1.27 (d, J=6.40 Hz, 3H).

Example 91(S)-1-cyano-N-(5-morpholinothiazol-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 3)

Step a.

To a solution of morpholine (11.17 mmol) in MeCN (15 ml) was addedCs₂CO₃ (16.75 mmol) at rt. The reaction mixture was stirred for 5 min.5-Bromothiazol-2-amine (5.58 mmol) was added to the reaction mixture andstirred at rt for 2 h. The resulting reaction mixture was poured intowater (100 ml) and extracted with EtOAc (3×50 ml). The combined organicphase was collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography (2% MeOH in DCM) yielding 5-morpholinothiazol-2-amine(1.83 mmol). MS: ES+ 186.05; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.49 (s,2H), 6.28 (s, 1H), 3.64-3.67 (m, 4H), 2.79-2.80 (m, 4H).

Steps b-d.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 1 using(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid. MS: ES+308.33; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.97 (s, 1H), 6.69 (s, 1H),3.70-3.73 (m, 4H), 3.57-3.63 (m, 1H), 3.39-3.50 (m, 3H), 3.24-3.33 (m,1H), 2.97-3.00 (m, 4H), 2.10-2.21 (m, 1H), 1.97-2.10 (m, 1H).

Compounds in Table 3 were synthesised using a procedure similar to thatdescribed for Example 91 using 1-BOC-pyrrolidine-3-carboxylic acid.

TABLE 3 Amine CAS ¹H NMR Ex R1 Name Number (400 MHz, DMSO-d₆) δ ppm MS92

1-cyano-N-(5-(4- methylpiperazin- 1-yl)thiazol-2- yl)pyrrolidine-3-carboxamide 109-01-3 11.93 (s, 1 H), 6.64 (s, 1 H), 3.57-3.61 (m, 1 H),3.38- 3.52 (m, 3 H), 3.24-3.27 (m, 1 H), 2.95-3.00 (m, 4 H), 2.41-246(m, 4 H), 2.23 (s, 3 H), 2.13-2.18 (m, 1 H), 2.01- 2.04 (m, 1 H) ES−319.15 93

N-(5-(2- (acetamidomethyl) piperidin-1- yl)thiazol-2-yl)- 1-cyanopyrrolidine- 3-carboxamide 98998-26- 6 11.93 (s, 1 H), 7.86 (br s,1 H), 6.72 (s, 1 H), 3.56-3.63 (m, 1 H), 3.38-3.52 (m, 3 H), 3.13-3.28(m, 4 H), 2.99- 3.02 (m, 2 H), 2.13-2.17 (m, 1 H), 1.99-2.07 (m, 1 H),1.77 (s, 3 H), 1.46-1.62 (m, 6 H) ES+ 377.49 94

1-cyano-N-(5- (methyl(phenyl) amino)thiazol-2- yl)pyrrolidine-3-carboxamide 100-61-8 12.23 (s, 1 H), 7.21-7.28 (m, 3 H), 6.82-6.93 (m, 3H), 3.57-3.64 (m, 1 H), 3.47- 3.54 (m, 1 H), 3.38-3.47 (m, 2 H),3.28-3.31 (m, 1 H), 3.24 (s, 3 H), 2.12-2.22 (m, 1 H), 2.01-2.05 (m, 1H) ES+ 328.28 95

1-cyano-N-(5- (indolin-1- yl)thiazol-2- yl)pyrrolidine-3- carboxamide496-15-1 12.18 (s, 1 H), 7.18 (d, J = 7.32 Hz, 1 H), 7.09-7.14 (m, 2H),6.88 (d, J = 7.93 Hz, 1 H), 6.78 (t, J = 7.47 Hz, 1 H), 3.87 (t, J =8.54 Hz, 2 H), 3.59-3.65 (m, 1 H), 3.49-3.55 (m, 1 H), 3.40-3.49 (m, 2H), 3.27- 3.33 (m, 1 H), 3.16 (t, J = 8.54 Hz, 2 H), 2.14-2.23 (m, 1 H),2.01-2.11 (m, 1 H) ES+ 340.18

Compounds in Table 4 were synthesised using a procedure similar to thatdescribed for Example 91 using(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid.

TABLE 4 Amine CAS ¹H NMR Ex R1 Name Number (400 MHz, DMSO-d₆) δ ppm MS96

(S)-1-cyano-N- (5-(piperidin-1- yl)thiazol-2- yl)pyrrolidine-3-carboxamide 110-89-4 11.90 (s, 1 H), 6.62 (s, 1 H), 3.56-3.63 (m, 1 H),3.47- 3.51 (m, 1 H), 3.38-3.45 (m, 2 H), 3.21-3.31 (m, 1 H), 2.95-3.00(m, 4 H), 2.10- 2.21 (m, 1 H), 1.97-2.07 (m, 1 H), 1.59-1.65 (m, 4 H),1.46-1.54 (m, 2 H) ES+ 306.27 97

(S)-1-cyano-N- (5-(isoindolin-2- yl)thiazol-2- yl)pyrrolidine-3-carboxamide 496-12-8 11.93 (s, 1 H), 7.37-7.40 (m, 2 H), 7.30-7.33 (m, 2H), 6.46 (s, 1 H), 4.53 (s, 4 H), 3.58-3.64 (m, 1 H), 3.38- 3.53 (m, 3H), 3.24-3.30 (m, 1 H), 2.14-2.19 (m, 1 H), 2.01-2.09 (m, 1 H) ES+340.10 98

(S)-1-cyano-N- (5-(3,4- dihydroisoquinolin- 2(1H)- yl)thiazol-2-yl)pyrrolidine-3- carboxamide 91-21-4 11.97 (s, 1 H), 7.17-7.30 (m, 4H), 6.75 (s, 1 H), 4.25 (s, 2 H), 3.58-3.63 (m, 1 H), 3.37- 3.52 (m, 5H), 3.24-3.29 (m, 1 H), 2.90-2.95 (m, 2 H), 2.13-2.20 (m, 1 H), 2.00-2.05 (m, 1 H) ES+ 354.15 99

(S)-1-cyano-N- (5-((R)-2- (methoxymethyl) pyrrolidin-1- yl)thiazol-2-yl)pyrrolidine-3- carboxamide 84025-81- 0 11.85 (s, 1 H), 6.39 (s, 1 H),3.57-3.62 (m, 1 H), 3.45- 3.53 (m, 3 H), 3.36-3.45 (m, 2 H), 3.22-3.30(m, 6 H), 2.97-2.99 (m, 1 H), 2.13- 2.16 (m, 1 H), 1.84-2.05 (m, 5 H)ES+ 336.15 100

(S)-1-cyano-N- (5-((S)-2- (methoxymethyl) pyrrolidin-1- yl)thiazol-2-yl)pyrrolidine-3- carboxamide 63126-47- 6 11.71 (br s, 1 H), 6.33 (s, 1H), 3.69-3.80 (m, 2 H), 3.59- 3.69 (m, 2 H), 3.43-3.57 (m, 3 H),3.33-3.40 (m, 4 H), 3.20-3.23 (m, 1 H), 3.05- 3.17 (m, 1 H), 2.24-2.33(m, 2 H), 1.98-2.10 (m, 4 H) ES+ 336.78 101

(S)-1-cyano-N- (5-(5-oxo-1,4- diazepan-1- yl)thiazol-2-yl)pyrrolidine-3- carboxamide 34376-54- 0 11.99 (br s, 1 H), 7.68 (br s,1 H), 6.62 (s, 1 H), 3.57-3.62 (m, 1 H), 3.39-3.52 (m, 3 H), 3.21-3.33(m, 7 H), 2.51- 2.56 (m, 2 H), 2.11-2.21 (m, 1 H), 1.99-2.08 (m, 1 H)ES+ 335.33

Example 102(R)-1-cyano-N-(5-morpholinothiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 91using morpholine and (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylicacid. MS: ES+ 308.33; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.97 (s, 1H),6.69 (s, 1H), 3.70-3.73 (m, 4H), 3.57-3.63 (m, 1H), 3.39-3.50 (m, 3H),3.24-3.33 (m, 1H), 2.97-3.00 (m, 4H), 2.10-221 (m, 1H), 1.97-2.10 (m,1H).

Example 103(R)-1-cyano-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 91using piperidine and (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylicacid. MS: ES+ 305.9; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.89 (s, 1H), 6.61(s, 1H), 3.57-3.61 (m, 1H), 3.37-3.50 (m, 3H), 3.23-3.34 (m, 1H),2.95-3.00 (m, 4H), 2.09-2.21 (m, 1H), 1.97-2.08 (m, 1H), 1.57-1.69 (m,4H), 1.50 (m, 2H).

Example 104(±)-trans-1-cyano-4-methyl-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 91using piperidine and Intermediate 2. MS: ES+ 320.21; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.99 (s, 1H), 6.62 (s, 1H), 3.67-3.72 (m, 1H), 3.57-3.61(m, 1H), 3.45-3.49 (m, 1H), 3.02-3.06 (m, 1H), 2.96-3.00 (m, 4H),2.84-2.90 (m, 1H), 2.40-2.46 (m, 1H), 1.59-1.64 (m, 4H), 1.49-1.52 (m,2H), 1.01 (d, J=6.71 Hz, 3H).

Example 1051-cyano-5-methyl-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 91using piperidine and1-(tert-butoxycarbonyl)-5-methylpyrrolidine-3-carboxylic acid (preparedaccording to the method described in WO2010059658). MS: ES+ 320.38; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.89 (s, 1H), 6.62 (s, 1H), 3.67-3.71 (m,1H), 3.54-3.63 (m, 2H), 3.23-3.32 (m, 1H), 2.95-3.00 (m, 4H), 2.29-2.35(m, 1H), 1.56-1.66 (m, 5H), 1.49-1.52 (m, 2H), 1.25 (d, J=6.10 Hz, 3H).

Example 106(S)-1-cyano-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 91using 2-amino-6-bromopyridine, pyrrolidine and(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid. MS: ES+286.38; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.07 (s, 1H), 7.44 (t, J=7.93Hz, 1H), 7.27 (d, J=8.24 Hz, 1H), 6.16 (d, J=8.24 Hz, 1H), 3.56-3.62 (m,1H), 3.42-3.48 (m, 2H), 3.31-3.41 (m, 6H), 2.10-2.19 (m, 1H), 1.98-2.06(m, 1H), 1.90-1.97 (m, 4H).

Example 107(S)-1-cyano-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 91using 2-amino-4-bromopyridine, pyrrolidine and(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid. MS: ES+286.33; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.77 (d, J=6.40 Hz, 1H), 7.41 (s,1H), 6.27 (dd, J=6.4, 2.4 Hz, 1H), 3.59-3.77 (m, 3H), 3.45-3.54 (m, 1H),3.40-3.48 (m, 4H), 3.23-3.26 (m, 1H), 2.24-2.33 (m, 2H), 2.06-2.11 (m,4H).

Example 108(S)-1-cyano-N-(5-(pyrrolidin-1-yl)pyrazin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 91using 2-amino-5-bromopyrazine, pyrrolidine and(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid. MS: ES+287.48; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.42 (s, 1H), 8.73 (s, 1H),7.72 (d, J=1.52 Hz, 1H), 3.56-3.65 (m, 1H), 3.45-3.52 (m, 2H), 3.40-3.43(m, 5H), 3.25-3.29 (m, 1H), 2.13-2.16 (m, 1H), 2.01-2.06 (m, 1H),1.93-1.96 (m, 4H).

Example 109N-(5-(2-aminophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide(Prepared According to Scheme 4)

Step a.

A solution of 5-bromothiazol-2-amine (39.3 mmol) andBOC-1-pyrrolidine-3-carboxylic acid (32.5 mmol) in THF (50 ml) wasstirred at rt for 5 min. T3P (50% in EtOAc) (65.1 mmol) and TEA (97.6mmol) were added to the reaction mixture at rt. The reaction mixture wasstirred at rt for 16 h. The resulting reaction mixture was poured intowater (100 ml) and extracted with EtOAc (3×100 ml). The combined organicphase was collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by flashchromatography (45-50% EtOAc in hexane) yielding tert-butyl3-((5-bromothiazol-2-yl)carbamoyl)-pyrrolidine-1-carboxylate (12.88mmol). MS: ES+ 376.23; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.54 (s, 1H),7.58 (s, 1H), 3.50-3.54 (m, 1H), 3.36-3.40 (m, 2H), 3.24-3.34 (m, 2H),2.12-2.15 (m, 1H), 2.00-2.05 (m, 1H), 1.4 (s, 9H).

Step b.

A solution of tert-butyl3-((5-bromothiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate (0.26 mmol)and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.26 mmol)in 1,4-dioxane:water (1:1, 1 ml) was stirred at rt in a glass tube for 5min. Na₂CO₃ (1.06 mmol) was added to the reaction mixture and degassedfor 30 min. Pd(PPh₃)₄ (0.026 mol) was added and the glass tube wassealed. The reaction mixture was heated at 110° C. (externaltemperature) for 24 h. The resulting reaction mixture was poured intowater (150 ml) and extracted with EtOAc (3×50 ml). The combined organicphase was dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by column chromatography(45-50% EtOAc in hexane) yielding tert-butyl3-((5-(2-aminophenyl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(quantitative). MS: ES+ 389.30

Step c.

To a solution of tert-butyl3-((5-(2-aminophenyl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.38 mmol) in DCM (2 ml) was added 4M HCl in 1,4-dioxane (1.54 mmol) at0° C. The reaction mixture was stirred at rt for 24 h. The resultingreaction mixture was concentrated under reduced pressure. The obtainedresidue was triturated with diethyl ether (10 ml) yieldingN-(5-(2-aminophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide hydrochloride(0.34 mmol). This material was used directly for the next step withoutfurther purification. MS: ES+ 289.23

Step d.

To a solution ofN-(5-(2-aminophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide hydrochloride(0.34 mmol) in DCM (2 ml) was added TEA (1.38 mmol) and cyanogen bromide(0.5 mmol) at 0° C. The reaction mixture was stirred at rt for 30 min.The resulting reaction mixture was poured into water (20 ml) andextracted with DCM (3×20 ml). The combined organic phase was collected,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography (3-4% MeOH inDCM) yielding the title compound (0.05 mmol). MS: ES+ 314.16; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.35 (s, 1H), 7.56 (s, 1H), 7.13 (dd, J=7.63,1.52 Hz, 1H), 7.03-7.08 (m, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.59-6.64 (m,1H), 5.09 (br s, 2H), 3.61-3.66 (m, 1H), 3.52-3.56 (m, 1H), 3.40-3.48(m, 2H), 3.33-3.38 (m, 1H), 2.18-2.22 (m, 1H), 2.04-2.09 (m, 1H)Compounds in Table 5 were synthesised using a procedure similar to thatdescribed for Example 109 using 1-BOC-pyrrolidine-3-carboxylic acid.

TABLE 5 Boronic acid or boronate ester CAS ¹H NMR Ex R1 Name Number (400MHz, DMSO-d₆) δ ppm MS 110

N-(5-(3- aminophenyl)thi- azol-2-yl)-1- cyanopyrrolidine- 3- carboxamide30418-59- 8 12.36 (br s, 1 H), 7.71 (s, 1 H), 7.05 (t, J = 7.70 Hz, 1H), 6.73-6.80 (m, 2 H), 6.47- 6.54 (m, 1 H), 5.24 (br s, 2 H), 3.59-3.67(m, 1 H), 3.52- 3.59 (m, 1 H), 3.37-3.52 (m, 3 H), 2.14-2.26 (m, 1 H),2.03-2.13 (m, 1 H) ES+ 313.89 111

N-(5-(4- aminophenyl)thi- azol-2-yl)-1- cyanopyrrolidine- 3- carboxamide214360- 73-3 12.23 (s, 1 H), 7.56 (s, 1 H), 7.25 (d, J = 8.54 Hz, 2 H),6.58 (d, J = 8.54 Hz, 2 H), 5.33 (br s, 2 H), 3.58-3.67 (m, 1 H),3.50-3.57 (m, 1 H), 3.40- 3.49 (m, 2 H), 3.28-3.37 (m, 1 H), 2.18-2.21(m, 1 H), 2.05-2.10 (m, 1 H) ES+ 313.95 112

1-cyano-N-(5- (pyridin-3- yl)thiazol-2- yl)pyrrolidine- 3-carboxamide1692-25-7 12.53 (s, 1 H), 8.87 (d, J = 2.44 Hz, 1 H), 8.50 (dd, J =4.73, 1.68 Hz, 1 H), 8.05 (s, 1 H), 8.02 (dd, J = 2.44, 1.53 Hz, 1 H),7.42-7.48 (m, 1 H), 3.60- 3.68 (m, 1 H), 3.53-3.59 (m, 1 H), 3.40-3.51(m, 2 H), 3.34-3.31 (m, 1 H), 2.16- 2.29 (m, 1 II), 2.05-2.13 (m, 1H)ES+ 299.96 113

(E)-1-cyano-N- (5-(2- cyclopropylvinyl) thiazol-2- yl)pyrrolidine-3-carboxamide 903510- 64-5 12.26 (br s, 1 H), 7.28 (s, 1 H), 6.59 (d, J= 15.57 Hz, 1 H), 5.50 (dd, J = 15.41, 9.00 Hz, 1 H), 3.38-3.68 (m, 5H), 2.15- 2.20 (m, 1 H), 2.01-2.08 (m, 1 H), 1.44-1.61 (m, 1 H),0.71-0.82 (m, 2 H), 0.48- 0.49 (m, 2 H) ES+ 289.18 114

N-(5-(4- acetamidophenyl) thiazol-2-yl)- 1- cyanopyrrolidine- 3-carboxamide 101251- 09-6 12.38 (s, 1 H), 10.06 (s, 1 H), 7.80 (s, 1 H),7.61-7.71 (m, 2 H), 7.53-7.58 (m, 2 H), 3.60- 3.66 (m, 1 H), 3.52-3.55(m, 1 H), 3.40-3.50 (m, 2 H), 3.30-3.34 (m, 1 H), 2.16- 2.24 (m, 1 H),1.97-2.12 (m, 4 H) ES+ 355.89 115

N-(5-(2- acetamidophenyl) thiazol-2-yl)- 1- cyanopyrrolidine- 3-carboxamide 169760- 16-1 12.38 (s, 1 H), 9.63 (s, 1 H), 7.75 (s, 1 H),7.61 (d, J = 7.32 Hz, 1 H), 7.27-7.39 (m, 3 H), 3.61-3.67 (m, 1 H),3.53- 3.58 (m, 1 H), 3.41-3.47 (m, 2 H), 3.30-3.34 (m, 1 H), 2.17-2.24(m, 1 H), 2.05- 2.12 (m, 1 H), 2.02 (s, 3 H) ES+ 356.23 116

l-cyano-N-(5- (3- (methylsulfon- amido)phenyl)thiazol- 2-yl)pyrrolidine- 3-carboxamide 148355- 75-3 12.46 (br s, 1 H), 9.88 (brs, 1 H), 7.86 (s, 1 H), 7.37-7.42 (m, 3 H), 7.13-7.17 (m, 1 H),3.60-3.67 (m, 1 H), 3.53- 3.58 (m, 1 H), 3.37-3.48 (m, 2 H), 3.32-3.38(m, 1 H), 3.05 (s, 3 H), 2.16-2.25 (m, 1 H), 2.03-2.14 (m, 1 H) ES+391.79

Example 117(S)-1-cyano-N-(5-(3-cyanophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid and3-cyanophenylboronic acid in step b. MS: ES+ 324.33; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.49 (s, 1H), 8.12-8.22 (m, 1H), 8.08 (s, 1H), 7.88-7.96(m, 1H), 7.72-7.80 (m, 1H), 7.57-7.66 (m, 1H), 3.58-3.66 (m, 1H),3.50-3.57 (m, 1H), 3.34-3.48 (m, 3H), 2.16-2.30 (m, 1H), 2.00-2.15 (m,1H).

Example 118(S)-1-cyano-N-(5-(4-cyanophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid and4-cyanophenylboronic acid. MS: ES+ 324.48; ¹H NMR (400 MHz, DMSO-d₆) δppm 12.60 (s, 1H), 8.15 (s, 1H), 7.86-7.88 (m, 2H), 7.81-7.84 (m, 2H),3.61-3.66 (m, 1H), 3.54-3.59 (m, 1H), 3.40-3.49 (m, 2H), 3.36-3.40 (m,1H), 2.17-223 (m, 1H), 2.06-2.13 (m, 1H).

Example 1191-cyano-N-(5-(3,5-dimethylisoxazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using 2-amino-5-bromobenzothiazole in step a and3,5-dimethylisoxazole-4-boronic acid in step b. MS: ES+ 367.92; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.61 (s, 1H), 8.09 (d, J=8.24 Hz, 1H), 7.75(s, 1H), 7.33 (d, J=7.94 Hz, 1H), 3.53-3.72 (m, 2H), 3.39-3.49 (m, 3H),2.44 (s, 3H), 2.21-2.27 (m, 4H), 2.05-2.19 (m, 1H).

Compounds in Table 6 were synthesised using a procedure similar to thatdescribed for Example 109 using(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid and2-amino-6-bromobenzothiazole.

TABLE 6 Boronic acid or boronate ester CAS ¹H NMR (400 MHz, DMSO- Ex R1Name Number d₆) δ ppm MS 120

(S)-1-cyano-N-(6- (3,5- dimethylisoxazol- 4- yl)benzo[d]thiazol-2-yl)pyrrolidine- 3-carboxamide 16114-47- 9 12.65 (s, 1 H), 8.07 (d, J =1.53 Hz, 1 H), 7.83 (d, J = 8.24 Hz, 1 H), 7.44 (dd, J = 8.00, 2.00 Hz,1 H), 3.55-3.70 (m, 2 H), 3.39-3.51 (m, 3 H), 2.44 (s, 3 H), 2.20-2.26(m, 4 H), 2.02- 2.16 (m, 1 H) ES+ 368.23 121

(S)-1-cyano-N-(6- (4- methoxyphenyl) benzo[d]thiazol-2-yl)pyrrolidine-3- carboxamide 5720-07-0 12.60 (br s, 1 H), 8.26 (s, 1H), 7.78-7.80 (m, 1 H), 7.67- 7.71 (m, 3 H), 7.05-7.06 (m, 2 H), 3.81(s, 3 H), 3.60- 3.68 (m, 2 H), 3.34-3.48 (m, 3 H), 2.20-2.27 (m, 1 H),2.09-2.14 (m, 1 H) ES+ 379.58 122

(S)-1-cyano-N-(6- phenylbenzo[d] thiazol-2- yl)pyrrolidine-3-carboxamide 98-80-6 12.62 (br s, 1 H), 8.33 (d, J = 1.22 Hz, 1 H), 7.82(d, J = 8.4 Hz, 1 H), 7.73-7.76 (m, 3 H), 7.47-7.51 (m, 2 H), 7.37-7.39(m, 1 H), 3.64- 3.68 (m, 1 H), 3.57-3.61 (m, 1 H), 3.34-3.50 (m, 3 H),2.22-2.27 (m, 1 H), 2.09- 2.15 (m, 1 H) ES+ 349.38 123

(S)-1-cyano-N-(6- (1-methyl-1H- pyrazol-5- yl)benzo[d]thiazol-2-yl)pyrrolidine- 3-carboxamide 847818- 74-0 12.68 (s, 1 H), 8.21 (d, J= 1.83 Hz, 1 H), 7.84 (d, J = 8.54 Hz, 1 H), 7.59 (dd, J = 8.24, 1.83Hz, 1 H), 7.49 (d, J = 1.83 Hz, 1 H), 6.45 (d, J = 1.83 Hz, 1 H), 3.89(s, 3 H), 3.64-3.69 (m, 1 H), 3.58-3.62 (m, 1 H), 3.34- 3.52 (m, 3 H),2.21-2.29 (m, 1 H), 2.10-2.16 (m, 1 H) ES+ 353.07 124

(S)-1-cyano-N-(6- (1-methyl-1H- pyrazol-4- yl)benzo[d]thiazol-2-yl)pyrrolidine- 3-carboxamide 761446- 44-0 12.55 (s, 1 H), 8.17-8.19(m, 2 H), 7.91 (s, 1 H), 7.72 (d, J = 8.40 Hz, 1 H), 7.65 (dd, J = 8.4,2.0 Hz, 1 H), 3.88 (s, 3 H), 3.61-3.67 (m, 1 H), 3.51- 3.60 (m, 1 H),3.43-3.51 (m, 2 H), 3.38-3.41 (m, 1 H), 2.19-2.26 (m, 1 H), 2.08- 2.15(m, 1 H) ES+ 353.00 125

(S)-1-cyano-N-(6- (3,5-dimethyl-1H- pyrazol-4- yl)benzo[d]thiazol-2-yl)pyrrolidine- 3-carboxamide 1162262- 39-6 12.55 (s, 1 H), 12.31 (brs, 1 II), 7.90 (s, 1 II), 7.76 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 8.4Hz, 1 H) 3.56-3.66 (m, 2 H), 3.35-3.47 (m, 3 H), 2.22 (s, 6 H),2.15-2.21 (m, 1 H), 2.07- 2.13 (m, 1 H) ES+ 366.94 126

(S)-1-cyano-N-(6- (5- methylisoxazol-4- yl)benzo[d]thiazol-2-yl)pyrrolidine- 3-carboxamide 1346808- 41-0 12.63 (s, 1H), 8.92 (s,1H), 8.2 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 4.4 Hz, 1H), 7.61 (dd, J =8.8 Hz, 2.0 Hz, 1H), 3.57-3.68 (m, 2 H), 3.36-3.50 (m, 3 H), 2.63 (s,3H), 2.16-2.26 (m, 1 H), 2.09-2.14 (m, 1 H) ES+ 354.53

Example 127(S)-1-cyano-N-(7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid,2-amino-7-bromoimidazo[1,2-a]pyridine (prepared according to the methoddescribed in WO2005089763) and 3,5-dimethylisoxazole-4-boronic acid. MS:ES+ 351.08; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.94 (s, 1H), 8.62 (d,J=7.02 Hz, 1H), 8.16 (s, 1H), 7.45 (s, 1H), 6.94 (dd, J=7.02, 1.83 Hz,1H), 3.61-3.66 (m, 1H), 3.44-3.54 (m, 2H), 3.40-3.43 (m, 1H), 3.30-3.33(m, 1H), 2.47 (s, 3H), 2.29 (s, 3H), 2.16-2.21 (m, 1H), 2.05-2.10 (m,1H).

Example 128(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid,2-amino-6-bromoimidazo[1,2-a]pyridine (prepared according to the methoddescribed in WO2012174312) and 3,5-dimethylisoxazole-4-boronic acid. MS:ES+ 351.09; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.00 (br s, 1H), 8.66 (s,1H), 8.15 (s, 1H), 7.52 (d, J=9.20 Hz, 1H), 7.26 (dd, J=9.16, 1.53 Hz,1H), 3.49-3.52 (m, 1H), 3.44-3.48 (m, 1H), 3.38-3.42 (m, 2H), 3.28-3.31(m, 1H), 2.43 (s, 3H), 2.20 (s, 3H), 2.14-2.22 (m, 1H), 2.01-2.10 (m,1H).

Example 129(S)-1-cyano-N-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 4)

Step b.

A solution of tert-butyl(S)-3-((6-bromoimidazo[1,2-a]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.98 mmol) [prepared using a procedure similar to that described forExample 109 using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylicacid and 2-amino-7-bromoimidazo[1,2-a]pyridine (prepared according tothe method described in WO2005089763) in step a] and potassiumcyclopropyl trifluoroborate (1.96 mmol) in toluene:water (8:1, 9 ml) wasmixed in a glass tube. K₃PO₄ (1.96 mmol) was added to the reactionmixture at rt and degassed for 10 min. Pd(dppf)Cl₂.CH₂Cl₂ (0.098 mmol)was added to the reaction mixture at rt and the glass tube was tightlysealed and heated to 100° C. for 18 h. The resulting reaction mixturewas poured into water (100 ml) and extracted with EtOAc (2×100 ml). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography (4% MeOH in DCM) yielding tert-butyl(S)-3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate (0.45 mmol). MS: ES+ 371.5

Steps c-d.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 109, steps c and d. MS:ES+ 296.38; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.87 (s, 1H), 8.37 (d,J=0.9 Hz, 1H), 7.99 (s, 1H), 7.32 (d, J=9.6 Hz, 1H), 6.97 (dd, J=9.6,2.0 Hz, 1H), 3.59-3.61 (m, 1H), 3.40-3.51 (m, 2H), 3.26-3.34 (m, 2H),2.13-2.19 (m, 1H), 2.01-2.08 (m, 1H), 1.90-1.94 (m, 1H), 0.88-0.95 (m,2H), 0.66-0.70 (m, 2H).

Example 1301-cyano-N-(6-cyclopropylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 129using 2-amino-6-bromobenzothiazole and potassiumcyclopropyltrifluoroborate. MS: ES+ 312.90; ¹H NMR (400 MHz, CD₃OD) δppm 7.63 (d, J=8.40 Hz, 1H), 7.59 (d, J=1.60 Hz, 1H), 7.19 (dd, J=8.40,1.60 Hz, 1H), 3.70-3.74 (m, 2H), 3.50-3.64 (m, 3H), 2.18-2.39 (m, 2H),2.00-2.10 (m, 1H), 0.97-1.06 (m, 2H), 0.71-0.78 (m, 2H).

Example 131(S)-1-cyano-N-(6-(3,6-dimethoxypyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 4)

Step b.

A solution of tert-butyl(3S)-3-[(6-bromoimidazo[1,2-a]pyridin-2-yl)carbamoyl]pyrrolidine-1-carboxylate(0.61 mmol) [prepared using a procedure similar to that described forExample 109 using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylicacid and 2-amino-7-bromoimidazo[1,2-a]pyridine (prepared according tothe method described in WO2005089763) in step a] and3,6-dimethoxylpyridazine-4-boronic acid (1.22 mmol) in 1,4-dioxane:water(4:1, 5 ml) was stirred at rt in a glass tube for 5 min. CsF (1.83 mmol)was added to the reaction mixture at rt and degassed for 30 min.Pd(dppf)Cl₂.CH₂Cl₂ (0.06 mol) was added to the reaction mixture at rtand the glass tube was sealed. The resulting reaction mixture was heatedat 100° C. for 2 h. The resulting reaction mixture was poured into water(20 ml) and extracted with EtOAc (3×20 ml). The combined organic phasewas dried over Na₂SO₄, filtered and concentrated under reduced pressure.The resulting residue was purified by column chromatography (100% DCM)yielding tert-butyl(S)-3-((6-(3,6-dimethoxypyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate (0.44 mmol). MS: ES+ 469.91. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.94 (br s, 1H) 9.01 (s, 1H), 8.17 (s, 1H), 7.50-7.57(m, 2H), 7.39 (s, 1H), 4.02 (s, 3H), 4.06 (s, 3H), 3.51-3.53 (m, 1H),3.35-3.43 (m, 2H), 3.23-3.28 (m, 2H), 2.09-2.11 (m, 1H), 2.03-2.04 (m,1H), 1.41 (s, 9H).

Steps c-d.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 109, steps c and d. MS:ES+ 394.11; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.01 (s, 1H), 9.02 (s, 1H),8.19 (s, 1H), 7.49-7.57 (m, 2H), 7.40 (s, 1H), 4.04 (s, 3H), 4.00 (s,3H), 3.59-3.69 (m, 1H), 3.46-3.54 (m, 2H), 3.40-3.44 (m, 2H), 2.14-2.21(m, 1H), 1.99-2.10 (m, 1H).

Example 132(S)-1-cyano-N-(6-(3,6-dimethoxypyridazin-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 131using 2-amino-5-bromobenzothiazole and3,6-dimethoxylpyridazine-4-boronic acid. MS: ES+ 411.06; ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.69 (s, 1H), 8.34 (d, J=1.52 Hz, 1H), 7.83 (d,J=8.4 Hz, 1H), 7.75 (dd, J=2.0, 8.8 Hz, 1H), 7.31 (s, 1H), 4.01 (s, 3H),4.00 (s, 3H) 3.57-3.68 (m, 2H), 3.37-3.51 (m, 3H), 2.19-2.33 (m, 1H),2.07-2.16 (m, 1H).

Example 133(2S,3S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)benzo[d]thiazol-2-yl)-2-methyl-pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using Intermediate 1, 2-amino-6-bromobenzothiazole and3,5-dimethylisoxazole-4-boronic acid. Purification by preparative HPLC;mobile phase: (A) 100% n-hexane (B) 50% IPA/MeOH, column: YMC PACKSIL,250×20 mm, 5 μm, flow rate: 15 ml/min. MS: ES+ 382.10; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.64 (s, 1H), 8.05 (d, J=1.52 Hz, 1H), 7.83 (d, J=8.24Hz, 1H), 7.44 (dd, J=8.4, 2.0 Hz, 1H), 4.01-4.06 (m, 1H), 3.61-3.67 (m,1H), 3.41-3.48 (m, 1H), 3.34-3.47 (m, 1H), 2.43 (s, 3H), 2.26 (s, 3H),2.20-2.24 (m, 1H), 2.05-2.14 (m, 1H), 1.14 (d, J=6.71 Hz, 3H).

Example 1341-cyano-N-(5-((p-tolyl)pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using 2-amino-5-bromo-pyridine and 4-methylphenylboronic acid. MS: ES+307.23; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.82 (s, 1H), 8.64 (d, J=2.0Hz, 1H), 8.13-8.20 (m, 1H), 8.07-8.12 (m, 1H), 7.62 (d, J=8.24 Hz, 2H),7.29 (d, J=7.94 Hz, 2H), 3.59-3.66 (m, 1H), 3.38-3.55 (m, 4H), 2.35 (s,3H), 2.14-2.23 (m, 1H), 2.01-2.11 (m, 1H).

Example 135 1-cyano-N-(5-(m-tolyl)pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using 2-amino-5-bromo-pyridine and 3-methylphenylboronic acid. MS: ES+307.23; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.84 (s, 1H), 8.66 (dd, J=2.44,0.61 Hz, 1H), 8.14-8.20 (m, 1H), 8.08-8.13 (m, 1H), 7.49-7.55 (m, 2H),7.37 (t, J=7.63 Hz, 1H), 7.21 (d, J=7.33 Hz, 1H), 3.59-3.66 (m, 1H),3.38-3.55 (m, 4H), 2.38 (s, 3H), 2.16-2.21 (m, 1H), 2.02-2.12 (m, 1H).

Example 136 1-cyano-N-(5-(o-tolyl)pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using 2-amino-5-bromo-pyridine and 2-methylphenylboronic acid. MS: ES+307.23; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.81 (s, 1H), 8.31 (d, J=2.44Hz, 1H), 8.16 (d, J=8.55 Hz, 1H), 7.82 (dd, J=8.55, 2.44 Hz, 1H),7.28-7.38 (m, 3H), 7.23-7.27 (m, 1H), 3.59-3.67 (m, 1H), 3.36-3.56 (m,4H), 2.25 (s, 3H), 2.14-2.23 (m, 1H), 2.03-2.13 (m, 1H).

Example 137(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)-5-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid,Intermediate 16 and 3,5-dimethylisoxazole-4-boronic acid. MS: ES+365.23; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.02 (s, 1H), 7.95 (s, 1H),7.44 (d, J=9.2, 1H), 7.15 (d, J=9.2, 1H), 3.62-3.66 (m, 1H), 3.42-3.54(m, 3H), 3.30-3.34 (m, 1H), 2.41 (s, 3H), 2.27 (s, 3H), 2.15-2.23 (m,1H), 2.09 (s, 3H), 2.02-2.08 (m, 1H).

Example 138(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)-7-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 5)

Step a.

A solution of Intermediate 15 (1.23 mmol) and3,5-dimethylisoxazole-4-boronic acid (2.46 mmol) inethanol:toluene:water (1:2:1, 10 ml) was stirred at rt in a glass tubefor 5 min. Na₂CO₃ (2.46 mmol) was added to the reaction mixture andpurged using nitrogen for 20 min. Pd(PPh₃)₄ (0.12 mmol) was added to thereaction mixture and the glass tube was sealed. The resulting reactionmixture was heated at 100° C. (external temperature) for 3 h. Theresulting reaction mixture was poured into water (100 ml) and extractedwith EtOAc (2×80 ml). The combined organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (40% EtOAc in hexane) yielding a75:25 mixture of6-(3,5-dimethyl-1,2-oxazol-4-yl)-7-methyl-1,3-benzothiazol-2-amine &6-(3,5-dimethyl-1,2-oxazol-4-yl)-5-methyl-1,3-benzothiazol-2-amine (0.54mmol). MS: ES+ 260.33.

Step b.

To a solution of (3S)-BOC-1-pyrrolidine-3-carboxylic acid (0.97 mmol)and DIPEA (1.62 mmol) in DCM (5 ml) was added HBTU (1.2 mmol) at rt andthe reaction mixture was stirred for 30 mins. A solution of 75:25mixture of6-(3,5-dimethyl-1,2-oxazol-4-yl)-7-methyl-1,3-benzothiazol-2-amine &6-(3,5-dimethyl-1,2-oxazol-4-yl)-5-methyl-1,3-benzothiazol-2-amine (0.81mmol) in DCM (5 ml) was added dropwise to the reaction mixture andstirred at rt for 2 h. The resulting reaction mixture was poured intowater (100 ml) and basified using solid NaHCO₃. The resulting mixturewas extracted with EtOAc (2×80 ml). The combined organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography(38% EtOAc in hexane) yielding a 80:20 mixture of tert-butyl(S)-3-((6-(3,5-dimethylisoxazol-4-yl)-7-methylbenzo[d]thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate& tert-butyl(S)-3-((6-(3,5-dimethylisoxazol-4-yl)-5-methylbenzo[d]thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(1.24 mmol). MS: ES+ 456.91.

Step c.

To a solution of a 80:20 mixture of tert-butyl(S)-3-((6-(3,5-dimethylisoxazol-4-yl)-7-methylbenzo[d]thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate& tert-butyl(S)-3-((6-(3,5-dimethylisoxazol-4-yl)-5-methylbenzo[d]thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.43 mmol) in DCM (5 ml) was added TFA (1 ml) at 0° C. The reactionmixture was stirred at rt for 1 h. The resulting reaction mixture wasconcentrated under reduced pressure. The obtained residue wasazetropically distilled using DCM to yielding a 80:20 mixture of(S)—N-(6-(3,5-dimethylisoxazol-4-yl)-7-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide&(S)—N-(6-(3,5-dimethylisoxazol-4-yl)-5-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamideTFA salt (quantitative) This material was used directly for the nextstep without further purification. MS: ES+ 357.48.

Step d.

To a solution of a 80:20 mixture of(S)—N-(6-(3,5-dimethylisoxazol-4-yl)-7-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide&(S)—N-(6-(3,5-dimethylisoxazol-4-yl)-5-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamideTFA salt (0.71 mmol) in THF (5 ml) was added K₂CO₃ (7.1 mmol) at rt.Cyanogen bromide (0.56 mmol) was added to the reaction mixture at 0° C.and stirred for 10 min. The resulting reaction mixture was poured intowater (150 ml) and extracted with EtOAc (2×80 ml). The combined organicphase was collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by flashchromatography (72% EtOAc in hexane) yielding 70:30 mixture of(3S)-1-cyano-N-[6-(3,5-dimethyl-1,2-oxazol-4-yl)-7-methyl-1,3-benzothiazol-2-yl]pyrrolidine-3-carboxamide&(3S)-1-cyano-N-[6-(3,5-dimethyl-1,2-oxazol-4-yl)-5-methyl-1,3-benzothiazol-2-yl]pyrrolidine-3-carboxamide(0.17 mmol). The regio-isomers were separated by preparative chiralHPLC; mobile phase: (A) 75-70% 10 mM aq NH₄OAc (B) 25-30% MeCN, column:Sunfire C18, 250×19 mm, 5 μm, flow rate: 19 ml/min, yielding the titlecompound (0.057 mmol). MS: ES+ 382.43; ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.64 (br s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H),3.57-3.66 (m, 2H), 3.42-3.47 (m, 2H), 3.32-3.36 (m, 1H), 2.28 (s, 3H),2.23 (s, 3H), 2.18-2.22 (m, 1H), 2.10-2.13 (m, 1H), 2.05 (s, 3H).

Example 139(S)-1-cyano-N-(7-methyl-6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 138using 1-methyl-1H-pyrazole-4-boronic acid pinacol ester. MS: ES+ 366.3;¹H NMR (400 MHz, DMSO-d₆) b ppm 12.56 (s, 1H), 7.97 (s, 1H), 7.68 (s,1H), 7.61 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 3.90 (s, 3H),3.63-3.68 (m, 1H), 3.56-3.60 (m, 1H), 3.43-3.49 (m, 2H), 3.37-3.42 (m,1H), 2.55 (s, 3H), 2.21-2.28 (m, 1H), 2.07-2.19 (m, 1H).

Example 1401-cyano-N-(5-(morpholinomethyl)thiazol-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 6)

Step a.

A solution of 2-amino-5-formylthiazole (15.6 mmol),1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (19.5 mmol) andHOAt (18.7 mmol) in DMF (20 ml) was stirred at rt for 5 min. DIPEA (21.8mmol) and EDC.HCl (18.7 mmol) were added to the reaction mixture andstirred for a further 3 h at rt. The resulting reaction mixture waspoured into water (200 ml) and extracted with EtOAc (2×50 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (60% EtOAc in hexane) yielding tert-butyl3-((5-formylthiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate (4.6 mmol).MS: ES+ 326.20; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.91 (s, 1H), 9.97 (s,1H), 8.44 (s, 1H), 3.63-4.02 (m, 1H), 3.27-3.36 (m, 4H), 2.11-2.22 (m,1H), 1.99-2.10 (m, 1H), 1.45 (s, 9H).

Step b.

To a solution of3-((5-formylthiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate (1.5 mmol)and morpholine (0.8 mmol) in DCE (10 ml) was added sodiumtriacetoxyborohydride (1.5 mmol) at rt and stirred for 3 h. Theresulting reaction mixture was poured into water (50 ml) and extractedwith EtOAc (2×25 ml). The combined organic phase dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (25% EtOAc in hexane) yieldingtert-butyl 3-((5-(morpholinomethyl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate (1.2 mmol). MS: ES+ 397.33; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.16 (s, 1H), 7.30 (s, 1H), 3.49-3.62 (m, 6H), 3.35-3.39(s, 3H), 3.19-3.31 (m, 2H), 2.31-2.37 (m, 4H), 2.05-2.15 (m, 1H),1.92-2.01 (m, 1H), 1.40 (s, 9H).

Step c.

To a solution of tert-butyl3-((5-(morpholinomethyl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(1.2 mmol) in DCM (4 ml) was added TFA (0.6 ml) at 0° C. The reactionmixture was stirred at rt for 40 min. The resulting reaction mixture wasconcentrated under reduced pressure. The obtained residue wasazeotropically distilled using DCM yieldingN-(5-(morpholinomethyl)thiazol-2-yl)pyrrolidine-3-carboxamide TFA salt(1.0 mmol). This material was used directly for the next step withoutfurther purification.

Step d.

To a solution ofN-(5-(morpholinomethyl)thiazol-2-yl)pyrrolidine-3-carboxamide TFA salt(1.0 mmol) in THF (4 ml) was added K₂CO₃ (3.0 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 30 min. Cyanogen bromide (1.1mmol) was added to the reaction mixture at 0° C. The reaction mixturewas then stirred at rt for 2 h. The resulting reaction mixture waspoured into water (30 ml) and extracted with EtOAc (20 ml) The organicphase was collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by flashchromatography (7-8% MeOH in DCM) yielding the title compound (0.08mmol). MS: ES+ 322.23; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.20 (br s, 1H),7.30 (s, 1H), 3.56-3.63 (m, 3H), 3.46-3.60 (m, 4H), 3.40-3.44 (m, 2H),3.20-3.30 (m, 2H), 2.30-2.48 (m, 4H), 2.15-2.18 (m, 1H), 2.02-2.07 (m,1H).

Example 1411-cyano-N-(5-(pyrrolidin-1-ylmethyl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 140using pyrrolidine. MS: ES+ 306.38; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.29(s, 1H), 7.29 (s, 1H), 3.72 (s, 2H), 3.59-3.63 (m, 1H), 3.49-3.53 (m,1H), 3.40-3.46 (m, 2H), 3.29-3.34 (m, 1H), 2.45 (m, 4H), 2.12-2.23 (m,1H), 2.01-2.12 (m, 1H), 1.69 (m, 4H).

Example 142(3S)-1-cyano-N-(5-((2,6-dimethylmorpholino)methyl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 140using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid and2,6-dimethyl-morpholine. MS: ES+ 350.43; H NMR (400 MHz, DMSO-d₆) δ ppm12.22 (br s, 1H), 7.30 (s, 1H), 3.62 (m, 4H), 3.28-3.55 (m, 5H),2.67-2.70 (m, 2H), 2.11-2.27 (m, 1H), 2.05-2.07 (m, 1H), 1.64 (t,J=10.84 Hz, 2H), 1.03 (d, J=6.41 Hz, 6H).

Example 143(S)-1-cyano-N-(5-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 140using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid and(R)-2-(methoxymethyl)pyrrolidine. MS: ES+ 349.98; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.19 (s, 1H), 7.27 (s, 1H), 4.10 (d, J=14.04 Hz, 1H),3.50-3.67 (m, 2H), 3.42-3.46 (m, 1H), 3.37-3.45 (m, 2H), 3.20-3.32 (m,6H), 2.79-2.87 (m, 1H), 2.65-2.74 (m, 1H), 2.09-2.27 (m, 2H), 1.97-2.10(m, 1H), 1.77-1.87 (m, 1H), 1.56-1.68 (m, 2H), 1.48 (m, 1H).

Example 144(S)-1-cyano-N-(5-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 140using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid and(S)-2-(methoxymethyl)pyrrolidine. MS: ES+ 349.98; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.19 (s, 1H), 7.27 (s, 1H), 4.10 (d, J=14.04 Hz, 1H),3.59-3.68 (m, 2H), 3.49-3.53 (m, 1H), 3.37-3.47 (m, 3H), 3.20-3.31 (m,5H), 2.73-2.89 (m, 1H), 2.60-2.75 (m, 1H), 2.08-2.27 (m, 2H), 1.99-2.08(m, 1H), 1.75-1.87 (m, 1H), 1.54-1.71 (m, 2H), 1.45-1.48 (m, 1H).

Example 145(2S,3S)-1-cyano-N-(5-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)-2-methylpyrrolidine-3-carboxamide(Prepared According to Scheme 7)

Step a.

To a solution of 2-aminothiazole-5-carbaldehyde (3.9 mmol) in THF (10ml) was added DMAP (5.85 mmol) and (BOC)₂O (5.85 mmol) at 0° C. Thereaction mixture was stirred at rt for 1 h. The resulting reactionmixture was poured into water (50 ml) and extracted with EtOAc (3×100ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (40% EtOAc in hexane) yieldingtert-butyl (5-formylthiazol-2-yl) carbamate (2.63 mmol). This materialwas used directly for the next step without further purification. MS:ES+ 229.05.

Step b.

To a solution of tert-butyl (5-formylthiazol-2-yl) carbamate (2.19 mmol)and (R)-2-(methoxymethyl) pyrrolidine (4.83 mmol) in MeOH (5 ml) wasadded sodium triacetoxyborohydride (3.28 mmol) at rt. The reactionmixture was heated at 80° C. for 2 h. The resulting reaction mixture waspoured into aqueous 1M HCl (50 ml) and extracted with EtOAc (2×25 ml).The organic layer was discarded. The aqueous layer was basified withsolid Na₂CO₃. The resulting mixture was extracted with EtOAc (2×50 ml).The combined organic phase was collected, dried over Na₂SO₄, filteredand concentrated under reduced pressure yielding tert-butyl(R)-(5-((2-(methoxymethyl) pyrrolidin-1-yl) methyl) thiazol-2-yl)carbamate (1.56 mmol). This material was used directly for the next stepwithout further purification. MS: ES+ 328.48; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 11.29 (s, 1H), 7.14 (s, 1H), 4.06 (d, J=14.4 Hz, 1H), 3.62 (d,J=14.4 Hz, 1H), 3.34-3.38 (m, 1H), 3.23-3.29 (m, 3H), 3.19-3.22 (m, 1H),2.82-2.86 (m, 1H), 2.67-2.70 (m, 1H), 2.18-2.24 (m, 1H), 1.77-1.85 (m,1H), 1.57-1.63 (m, 3H), 1.47 (s, 9H).

Step c.

To a solution of tert-butyl (R)-(5-((2-(methoxymethyl) pyrrolidin-1-yl)methyl) thiazol-2-yl) carbamate (1.56 mmol) in DCM (6 ml) was added TFA(2.5 ml) at 0° C. The reaction mixture was stirred at rt for 1 h. Theresulting reaction mixture was concentrated under reduced pressure. Theobtained residue was neutralized by aqueous solution of saturatedNaHCO₃. The resulting mixture was extracted with DCM (2×100 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding (R)-5-((2-(methoxymethyl)pyrrolidin-1-yl) methyl)thiazol-2-amine (quantitative). This materialwas used directly for the next step without further purification. MS:ES+ 228.04.

Step d.

To a solution of(2S,3S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-3-carboxylic acid(1.74 mmol) in THF (6 ml) was added T3P (50% in EtOAc) (5.24 mmol) atrt. The reaction mixture was stirred for 30 min and then cooled to 0° C.(R)-5-((2-(methoxymethyl) pyrrolidin-1-yl)methyl)thiazol-2-amine (1.57mmol) and DIPEA (5.24 mmol) were added and the reaction mixture wasstirred at rt for 1 h. The resulting reaction mixture was poured intosaturated NaHCO₃ (25 ml) and extracted with EtOAc (3×50 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding tert-butyl(2S,3S)-3-((5-(((R)-2-(methoxymethyl) pyrrolidin-1-yl) methyl)thiazol-2-yl) carbamoyl)-2-methylpyrrolidine-1-carboxylate (0.52 mmol).This material was used directly for the next step without furtherpurification. MS: ES+ 439.25; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.09 (brs, 1H), 7.26 (s, 1H), 4.18-4.22 (m, 1H), 4.08-4.11 (m, 1H), 3.63-3.66(m, 1H), 3.34-3.39 (m, 2H), 3.26 (s, 3H), 3.16-3.22 (m, 3H), 2.81-2.93(m, 1H), 2.67-2.69 (m, 1H), 2.19-2.25 (m, 2H), 1.90-1.93 (m, 1H),1.80-1.85 (m, 1H), 1.58-1.63 (m, 2H), 1.47-1.50 (m, 1H), 1.47 (s, 9H),0.90 (d, J=5.2 Hz, 3H).

Step e.

To a solution of tert-butyl(2S,3S)-3-((5-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)carbamoyl)-2-methylpyrrolidine-1-carboxylate (0.52 mmol) in DCM (10 ml)was added TFA (1.0 ml) at 0° C. The reaction mixture was stirred at rtfor 1 h. The resulting reaction mixture was concentrated under reducedpressure. The obtained residue was triturated with diethyl ether (10 ml)yielding (2S,3S)—N-(5-(((R)-2-(methoxymethyl) pyrrolidin-1-yl) methyl)thiazol-2-yl)-2-methylpyrrolidine-3-carboxamide TFA salt (0.409 mmol).This material was used directly for the next step without furtherpurification. MS: ES+ 339.10.

Step f.

To a solution of(2S,3S)—N-(5-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)-2-methylpyrrolidine-3-carboxamideTFA salt (0.409 mmol) in THF (6 ml) was added K₂CO₃ (1.2 mmol) at 0° C.The reaction mixture was stirred at 0° C. for 30 min. Cyanogen bromide(0.60 mmol) was added to the reaction mixture at 0° C. The reactionmixture was stirred at rt for 1 h. The resulting reaction mixture waspoured into water (30 ml). The resulting solid precipitates werecollected by filtration under reduced pressure and dried yielding thetitle compound (0.09 mmol). MS: ES+ 364.15; ¹H NMR (400 MHz, DMSO-d₆) δppm 12.16 (br s, 1H), 7.27 (s, 1H), 4.08-4.12 (m, 1H), 3.97-4.01 (m,1H), 3.63-3.67 (m, 2H), 3.35-3.42 (m, 4H), 3.26 (s, 3H), 2.83-2.87 (m,1H), 2.62-2.69 (m, 1H), 2.15-2.28 (m, 2H), 2.03-2.11 (m, 1H), 1.75-1.83(m, 1H), 1.55-1.70 (m, 2H), 1.49-1.51 (m, 1H), 0.87 (d, J=5.2 Hz, 3H).

Example 146(S)—N-(1-benzyl-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide

(Prepared According to Scheme 8, Steps c,f,h,i,j)

Step c.

To a solution of 4-nitro-1H-imidazole (4.42 mmol) in DMSO (5 ml) wereadded KOH pellets (6.6 mmol) at rt. The reaction mixture was cooled to0° C. and treated with benzyl bromide (5.31 mmol). The reaction mixturewas stirred at rt for 3 h. The resulting reaction mixture was pouredinto water (50 ml) and extracted with EtOAc (3×50 ml). The combinedorganic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (1.5-2.5% MeOH in DCM) yielding1-benzyl-4-nitro-1H-imidazole (3.2 mmol). ¹H NMR (400 MHz, DMSO-d₆) δppm 8.50 (d, J=1.2 Hz, 1H), 8.01 (d, J=1.2 Hz, 1H), 7.34-7.43 (m, 5H),5.31 (s, 2H).

Step f.

A solution of 1-benzyl-4-nitro-1H-imidazole (2.46 mmol) in MeOH:water(1:1, 12 ml) was stirred at rt for 5 min. Fe powder (12.3 mmol) andNH₄Cl (4.9 mmol) were added to the reaction mixture. The reactionmixture was heated at 80° C. for 2 h. The resulting reaction mixture wasallowed to cool to rt and poured into water (30 ml). The obtainedmixture was filtered through celite hyflow and washed with EtOAc (20ml). The organic layer was separated and the aqueous layer was extractedwith EtOAc (3×20 ml). The combined organic phase was collected, washedwith saturated NaHCO₃ solution (20 ml), dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding1-benzyl-1H-imidazol-4-amine (1.4 mmol). This material was immediatelyused for the next step without further purification. MS: ES+ 174.24.

Step h.

A solution of 1-benzyl-1H-imidazol-4-amine (1.4 mmol) and(3S)-BOC-1-pyrrolidine-3-carboxylic acid (1.4 mmol) in THF (3 ml) wasstirred at 0° C. for 5 min. T3P (50% in EtOAc) (2.1 mmol) and TEA (4.3mmol) was added to the reaction mixture and stirred at rt for 2 h. Theresulting reaction mixture was poured into water (40 ml) and extractedwith EtOAc (3×20 ml). The combined organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (2-3% MeOH in DCM) yieldingtert-butyl(S)-3-((1-benzyl-1H-imidazol-4-yl)carbamoyl)pyrrolidine-1-carboxylate(0.80 mmol). MS: ES+ 371.33

Step i.

To a solution of tert-butyl(S)-3-((1-benzyl-1H-imidazol-4-yl)carbamoyl)pyrrolidine-1-carboxylate(0.80 mmol) in DCM (6 ml) was added 4M HCl in 1,4-dioxane (24 mmol) at0° C. The reaction mixture was stirred at rt for 1 h. The resultingreaction mixture was concentrated under reduced pressure. The obtainedresidue was triturated with diethyl ether (10 ml) yielding(S)—N-(1-benzyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide hydrochloride(0.65 mmol). This material was used directly for the next step withoutfurther purification. MS: ES+ 271.33.

Step j.

To a solution of(S)—N-(1-benzyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide hydrochloride(0.65 mmol) in DMF (4 ml) was added K₂CO₃ (1.95 mmol) and cyanogenbromide (0.78 mmol) at 0° C. The reaction mixture was stirred at rt for30 min. The resulting reaction mixture was poured into water (40 ml) andextracted with EtOAc (3×20 ml). The combined organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography(2.5-3.5% MeOH in DCM) yielding the title compound (0.14 mmol). MS: ES+296.01; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.53 (s, 1H), 7.60 (d, J=1.2Hz, 1H), 7.35-7.38 (m, 2H), 7.27-7.33 (m, 3H), 7.21 (d, J=1.2 Hz, 1H),5.14 (s, 2H), 3.52-3.56 (m, 1H), 3.34-3.46 (m, 3H), 3.15-3.21 (m, 1H),2.04-2.10 (m, 1H), 1.93-2.00 (m, 1H).

Example 147(S)-1-cyano-N-(1-phenethyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 146using (2-bromoethyl)benzene in step c. MS: ES+ 310.01; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.47 (s, 1H), 7.27-7.30 (m, 4H), 7.19-7.23 (m, 3H), 4.16(t, J=7.32 Hz, 2H), 3.53-3.60 (m, 1H), 3.36-3.48 (m, 3H), 3.15-3.23 (m,1H), 3.01 (t, J=7.32 Hz, 2H), 2.06-2.15 (m, 1H), 1.97-2.05 (m, 1H).

Example 148(S)-1-cyano-N-(1-isobutyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 146using 1-bromo-2-methylpropane in step c. MS: ES+ 262.04; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.51 (s, 1H), 7.41 (d, J=1.52 Hz, 1H), 7.20 (d,J=1.52 Hz, 1H), 3.72 (d, J=7.32 Hz, 2H), 3.54-3.58 (m, 1H), 3.36-3.49(m, 3H), 3.17-3.21 (m, 1H), 2.05-2.15 (m, 1H), 1.92-2.04 (m, 2H), 0.82(d, J=6.71 Hz, 6H).

Example 149(2S,3S)—N-(1-benzyl-1H-imidazol-4-yl)-1-cyano-2-methylpyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 146using benzyl bromide and Intermediate 1. Purification by preparativeHPLC; mobile phase: (A) 100% n-hexane (B) 50% IPA/MeOH, column: YMCPACKSIL, 250×20 mm, 5 μm, flow rate: 20 ml/min. MS: ES+ 310.15; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.48 (s, 1H), 7.60 (d, J=1.60 Hz, 1H),7.35-7.39 (m, 2H), 7.29-7.33 (m, 3H), 7.22 (d, J=1.60 Hz, 1H), 5.13 (s,2H), 3.87-3.90 (m, 1H), 3.55-3.59 (m, 1H), 3.36-3.39 (m, 1H), 3.12-3.14(m, 1H), 2.06-2.09 (m, 1H), 1.92-1.96 (m, 1H), 1.04 (d, J=6.40 Hz, 3H).

Example 150(S)-1-cyano-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 8, Steps a,b,g,h,i,j)

Step a.

A solution of 4-nitro-1H-imidazole (8.84 mmol) in acetic acid (18 ml)was cooled to 0° C. Fuming HNO₃ (4.3 ml) was added dropwise to thereaction mixture. After completion of addition, acetic anhydride (12 ml)was added dropwise to the reaction mixture at 0° C. The reaction mixturewas stirred at rt for 2 h. The resulting reaction mixture was slowlypoured into ice water (100 ml) and extracted with EtOAc (3×50 ml). Thecombined organic phase was slowly washed with saturated K₂CO₃ solution(50 ml) (Exothermic Process), brine (50 ml) dried over Na₂SO₄, filteredand concentrated under reduced pressure yielding1,4-dinitro-1H-imidazole (8.8 mmol). This material was used directly forthe next step without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 8.53 (d, J=1.5 Hz, 1H), 8.40 (d, J=1.5 Hz, 1H).

Step b.

To a solution of 1,4-dinitro-1H-imidazole (1.25 mmol) in MeOH:water(1:1, 8 ml) was added 4-fluoroaniline (1.32 mmol) at rt. The reactionmixture was stirred at rt for 2 h. The resulting solid precipitates werecollected by filtration under reduced pressure and dried yielding1-(4-fluorophenyl)-4-nitro-1H-imidazole (0.96 mmol). This material wasused directly for the next step without further purification. MS: ES+208.23.

Step g.

To a solution of 1-(4-fluorophenyl)-4-nitro-1H-imidazole (0.97 mmol) inMeOH (5 ml) was added 10% Pd/C (0.5% w/w) at rt. The reaction mixturewas purged with H₂ gas for 2 h at rt. The resulting reaction mixture wascarefully filtered through celite hyflow and concentrated under reducedpressure to yield 1-(4-fluorophenyl)-1H-imidazol-4-amine (0.90 mmol).This material was used immediately for the next step without furtherpurification. MS: ES+: 177.96

Step h-j.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 146 according to Scheme8 steps h, i and j. MS: ES+ 300.23; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.73 (s, 1H), 8.08 (d, J=1.2 Hz, 1H), 7.66-7.70 (m, 3H), 7.33-7.38 (m,2H), 3.58-3.62 (m, 1H), 3.44-3.50 (m, 2H), 3.37-3.43 (m, 1H), 3.21-3.28(m, 1H), 2.10-2.18 (m, 1H), 1.98-2.07 (m, 1H).

Example 151(S)-1-cyano-N-(1-(3-fluorophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 3-fluoroaniline in step b. MS: ES+ 300.28; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.75 (s, 1H), 8.21 (d, J=1.52 Hz, 1H), 7.78 (d, J=1.52Hz, 1H), 7.62-7.67 (m, 1H), 7.50-7.59 (m, 2H), 7.16-7.23 (m, 1H),3.58-3.63 (m, 1H), 3.37-3.51 (m, 3H), 3.23-3.34 (m, 1H), 2.10-2.20 (m,1H), 1.98-2.08 (m, 1H).

Example 152(S)-1-cyano-N-(1-(2-fluorophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 2-fluoroaniline in step b. MS: ES+ 300.23; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.75 (br s, 1H), 8.22 (s, 1H), 7.78 (s, 1H), 7.63-7.65(m, 1H), 7.50-7.58 (m, 2H), 7.19-7.20 (m, 1H), 3.58-3.62 (m, 1H),3.29-3.58 (m, 3H), 3.22-3.29 (m, 1H), 2.10-2.19 (m, 1H), 1.98-2.08 (m,1H).

Example 153(S)-1-cyano-N-(1-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 4-(trifluoromethyl)aniline. MS: ES+ 350.1; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.77 (s, 1H), 8.31 (d, J=1.6 Hz, 1H), 7.84-7.92 (m, 5H),3.58-3.63 (m, 1H), 3.38-3.50 (m, 3H), 3.22-3.50 (m, 1H), 2.11-2.19 (m,1H), 1.99-2.08 (m, 1H).

Example 154(S)-1-cyano-N-(1-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 3-(trifluoromethyl)aniline. MS: ES+ 350.13; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.76 (s, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.35-8.47 (m, 1H),7.98 (d, J=7.2 Hz, 1H), 7.86 (d, J=1.2 Hz, 1H), 7.69-7.76 (m, 2H),3.58-3.63 (m, 1H), 3.38-3.50 (m, 3H), 3.24-3.29 (m, 1H), 2.11-2.17 (m,1H), 2.01-2.07 (m, 1H).

Example 155(S)-1-cyano-N-(1-(4-(methylcarbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 4-amino-N-methylbenzamide. MS: ES+ 339.23; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.77 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 8.25 (d, J=1.6 Hz,1H), 7.96 (d, J=8.8 Hz, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.76 (d, J=8.8 Hz,2H), 3.58-3.62 (m, 1H), 3.44-3.49 (m, 2H), 3.37-3.41 (m, 1H), 3.24-3.27(m, 1H), 2.79 (d, J=4.8 Hz, 3H), 2.12-2.17 (m, 1H), 2.00-2.05 (m, 1H).

Example 156(S)-1-cyano-N-(1-(3-(mnethylcarbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 3-amino-N-methylbenzamide. MS: ES+ 339.18; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.76 (s, 1H), 8.65 (d, J=4.8 Hz, 1H), 8.20 (d, J=1.6 Hz,1H), 8.02 (s, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.79-7.83 (m, 2H), 7.59 (t,J=8.0 Hz, 1H), 3.59-3.63 (m, 1H), 3.37-3.50 (m, 3H), 3.16-3.28 (m, 1H),2.81 (d, 4.4 Hz, 3H), 2.13-2.18 (m, 1H), 2.01-2.06 (m, 1H).

Example 157(S)-J-cyano-N-(1-(2-(methylcarbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 2-amino-N-methylbenzamide. MS: ES+ 339.18; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.67 (s, 1H), 8.36-8.39 (m, 1H), 7.62 (d, J=1.6 Hz, 1H),7.55-7.59 (m, 1H), 7.46-7.50 (m, 3H), 7.41 (d, J=1.6 Hz, 1H), 3.57-3.61(m, 1H), 3.36-3.49 (m, 3H), 3.20-3.27 (m, 1H), 2.64 (d, J=4.8 Hz, 3H),2.09-2.18 (m, 1H), 1.97-2.06 (m, 1H).

Example 158(S)-1-cyano-N-(1-(4-((2-methoxyethyl)carbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 4-amino-N-(2-methoxyethyl)benzamide. MS: ES+ 383.28; ¹H NMR (400MHz, DMSO-ds) δ ppm 10.77 (s, 1H), 8.63 (t, J=4.4 Hz, 1H), 8.27 (d,J=1.6 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.76 (d,J=8.8 Hz, 2H), 3.58-3.62 (m, 1H), 3.42-3.50 (m, 5H), 3.37-3.39 (m, 2H),3.27 (s, 3H), 3.22-3.26 (m, 1H), 2.11-2.17 (m, 1H), 1.98-2.05 (m, 1H).

Example 159(S)-1-cyano-N-(1-(4-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 4-methoxyaniline. MS: ES+ 312.18; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.70 (s, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.54 (d,J=8.8 Hz, 2H), 7.06 (d, J=9.2 Hz, 2H), 3.80 (s, 3H), 3.57-3.62 (m, 1H),3.44-3.48 (m, 2H), 3.37-3.42 (m, 1H), 3.22-3.26 (m, 1H), 2.11-2.16 (m,1H), 1.99-2.04 (m, 1H).

Example 160(S)-1-cyano-N-(1-(2-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 2-methoxyaniline. MS: ES+ 312.18; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.68 (s, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.39-7.45 (m, 3H), 7.25 (d, J=8.0Hz, 1H), 7.05-7.07 (m, 1H), 3.83 (s, 3H), 3.57-3.61 (m, 1H), 3.44-3.49(m, 2H), 3.34-3.42 (m, 1H), 3.22-3.26 (m, 1H), 2.09-2.17 (m, 1H),1.99-2.06 (m, 1H).

Example 161(S)-1-cyano-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 4-amino-tetrahydropyran. MS: ES+ 290.53; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 10.51 (s, 1H), 7.56 (d, J=1.60 Hz, 1H), 7.29 (d, J=1.60 Hz, 1H),4.21-4.27 (m, 1H), 3.93-3.97 (m, 2H), 3.54-3.58 (m, 1H), 3.37-3.48 (m,5H), 3.17-3.21 (m, 1H), 2.06-2.12 (m, 1H), 1.82-2.03 (m, 5H).

Example 162(S)-1-cyano-N-(1-cyclohexyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using cyclohexylamine. MS: ES+ 288.15; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.51 (s, 1H), 7.53 (d, J=1.2 Hz, 1H), 7.28 (d, J=1.6 Hz, 1H), 3.94-3.98(m, 1H), 3.54-3.58 (m, 1H), 3.36-3.48 (m, 3H), 3.17-3.21 (m, 1H),2.08-2.12 (m, 1H), 1.93-2.01 (m, 3H), 1.75-1.85 (m, 2H), 1.56-1.66 (m,4H), 1.31-1.41 (m, 2H).

Example 163(S)-1-cyano-N-(1-cyclohexyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using (±)-1-aminoindane. MS: ES+ 322.58; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.54 (s, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.31 (t,J=7.2 Hz, 1H), 7.22 (t, J=7.2 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 7.00 (d,J=1.2 Hz, 1H), 5.79 (t, J=6.8 Hz, 1H), 3.51-3.56 (m, 1H), 3.36-3.43 (m,3H), 3.15-3.18 (m, 1H), 3.07-3.13 (m, 1H), 2.89-2.97 (m, 1H), 2.60-2.67(m, 1H), 2.13-2.19 (m, 1H), 2.05-2.10 (m, 1H), 1.92-1.98 (m, 1H).

Example 164(S)-1-cyano-N-(1-(2,3-dihydro-1H-inden-2-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 2,3-dihydro-1H-inden-2-amine. MS: ES+ 322.58; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.51 (s, 1H), 7.54 (d, J=1.60 Hz, 1H), 7.30 (dd, J=5.20,3.20 Hz, 2H), 7.23 (dd, J=5.20, 2.00 Hz, 2H), 7.10 (d, J=1.60 Hz, 1H),5.01-5.10 (m, 1H), 3.51-3.57 (m, 1H), 3.36-3.47 (m, 5H), 3.08-3.18 (m,3H), 2.05-2.10 (m, 1H), 1.93-1.99 (m, 1H).

Example 165(S)-1-cyano-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 4-(aminomethyl)tetrahydropyran. MS: ES+ 304.25; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.52 (s, 1H), 7.43 (s, 1H), 7.23 (s, 1H), 3.81-3.83 (m,4H), 3.54-3.58 (m, 1H), 3.43-3.46 (m, 2H), 3.17-3.26 (m, 4H), 2.08-2.11(m, 1H), 1.96-2.01 (m, 1H), 1.89-1.90 (m, 1H), 1.36-1.39 (m, 2H),1.13-1.24 (m, 2H).

Example 166(S)-1-cyano-N-(1-((S)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using (S)-(−)-1-methylbenzylamine in step b. The reduction step wasperformed as described in Example 146 (Fe, NH₄Cl, MeOH, H₂O, 80° C.).MS: ES+ 310.10; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.54 (s, 1H), 7.66 (d,J=1.22 Hz, 1H), 7.34-7.39 (m, 2H), 7.28-7.32 (m, 3H), 7.22 (d, J=1.52Hz, 1H), 5.47 (q, J=6.91 Hz, 1H), 3.51-3.57 (m, 1H), 3.35-3.48 (m, 3H),3.13-3.21 (m, 1H), 2.04-2.13 (m, 1H), 1.92-2.02 (m, 1H), 1.77 (d, J=7.01Hz, 3H).

Example 167(S)-1-cyano-N-(1-((R)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using (R)-(−)-1-methyl-benzylamine. MS: ES+ 310.23; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.54 (s, 1H), 7.66 (d, J=1.22 Hz, 1H), 7.34-7.39 (m,2H), 7.28-7.32 (m, 3H), 7.22 (d, J=1.52 Hz, 1H), 5.47 (q, J=6.91 Hz,1H), 3.51-3.57 (m, 1H), 3.35-3.48 (m, 3H), 3.13-3.21 (m, 1H), 2.0415-2.13 (m, 1H), 1.92-2.02 (m, 1H), 1.77 (d, J=7.01 Hz, 3H).

Example 168(S)-1-cyano-N-(1-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using 2-(chloromethyl)-pyridine hydrochloride. The reduction step wasperformed as described in Example 146 (10% Pd/C, MeOH, H₂, rt). MS: ES+297.53; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.54 (s, 1H), 8.54 (dd, J=4.52,1.12 Hz, 1H), 7.78-7.83 (m, 1H), 7.59 (d, J=1.20 Hz, 1H), 7.32-7.35 (m,1H), 7.21-7.25 (m, 2H), 5.24 (s, 2H), 3.53-3.57 (m, 1H), 3.37-3.50 (m,3H), 3.15-3.22 (m, 1H), 2.05-2.13 (m, 1H), 1.94-2.01 (m, 1H).

Example 169(S)-1-cyano-N-(1-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 146using 3-(chloromethyl)-pyridine hydrochloride. The reduction step wasperformed as described in Example 150 (10% Pd/C, MeOH, H₂, rt). MS: ES+297.43; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1H), 8.53-8.57 (m,2H), 7.65-7.71 (m, 2H), 7.39-7.42 (m, 1H), 7.26 (s, 1H), 5.20 (s, 2H),3.52-3.56 (m, 1H), 3.34-3.46 (m, 3H), 3.15-3.19 (m, 1H), 2.04-2.10 (m,1H), 1.93-2.00 (m, 1H).

Example 170(S)-1-cyano-N-(1-(pyridin-4-ylmethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 146using 4-(chloromethyl)-pyridine hydrochloride. The reduction step wasperformed as described in Example 150 (10% Pd/C, MeOH, H₂, rt). MS: ES+297.48; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.59 (s, 1H), 8.55 (dd, J=4.40,1.60 Hz, 2H), 7.63 (d, J=1.20 Hz, 1H), 7.25 (d, J=1.20 Hz, 1H), 7.18(dd, J=4.36, 1.32 Hz, 2H), 5.23 (s, 2H), 3.53-3.58 (m, 1H), 3.37-3.47(m, 3H), 3.17-3.20 (m, 1H), 2.05-2.12 (m, 1H), 1.95-2.01 (m, 1H).

Example 171(S)-1-cyano-N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 146using 4-(chloromethyl)-3,5-dimethylisoxazole. The reduction step wasperformed as described in Example 150 (10% Pd/C, MeOH, H₂, rt). MS: ES+315.38; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.55 (s, 1H), 7.54 (d, J=1.00Hz, 1H), 7.13 (d, J=1.00 Hz, 1H), 5.00 (s, 2H), 3.53-3.57 (m, 1H),3.37-3.46 (m, 3H), 3.16-3.21 (m, 1H), 2.39 (s, 3H), 2.08 (s, 3H),2.06-2.16 (m, 1H), 1.92-2.00 (m, 1H).

Example 172(2S,3S)-1-cyano-2-methyl-N-(1-((S)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using (S)-(−)-1-methyl-benzylamine and Intermediate 1. The reductionstep was performed as described in Example 146 (Fe, NH₄Cl, MeOH, H₂O,80° C.). MS: ES+ 324.38; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.47 (s, 1H),7.65 (s, 1H), 7.23-7.63 (m, 5H), 7.25 (s, 1H), 5.47-5.48 (m, 1H),3.86-3.90 (m, 1H), 3.55-3.62 (m, 1H), 3.36-3.42 (m, 1H), 3.13-3.16 (m,1H), 2.07-2.09 (m, 1H), 1.91-1.99 (m, 1H), 1.78 (d, J=7.01 Hz, 3H), 1.06(d, J=6.71 Hz, 3H).

Example 173(3S,4S)-1-cyano-4-methyl-N-(1-((S)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 150using (S)-(−)-1-methyl-benzylamine and Intermediate 2. The reductionstep was performed as described in Example 146 (Fe, NH₄Cl, MeOH, H₂O,80° C.). MS: ES+ 324.43; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.59 (s, 1H),7.67 (s, 1H), 7.28-7.38 (m, 5H), 7.24-7.25 (m, 1H), 5.46-5.48 (m, 1H),3.55-3.65 (m, 2H), 3.36-3.40 (m, 1H), 2.97-3.01 (m, 1H), 2.76-2.83 (m,1H), 2.33-2.38 (m, 1H), 1.78 (d, J=7.02 Hz, 3H), 0.98 (d, J=6.10 Hz,3H).

Example 174(S)-1-cyano-N-(1-(4-methylpyridin-2-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 8, Steps d,g,h,i,j)

Step d.

A solution of 2-fluoro-4-methylpyridine (9.0 mmol), K₂CO₃ (27.0 mmol)and KI (9.0 mmol) in DMF (10 ml) was stirred at rt for 5 min.4-Nitroimidazole (9.0 mmol) was added to the reaction mixture and thenheated at 100° C. for 72 h. The resulting reaction mixture was pouredinto water (50 ml) and extracted with EtOAc (3×100 ml). The combinedorganic phase was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by flashchromatography (90-100% EtOAc in hexane) yielding4-methyl-2-(4-nitro-1H-imidazol-1-yl)pyridine (1.34 mmol). MS: ES+205.23; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.07 (d, J=1.2 Hz, 1H), 8.69 (d,J=1.2 Hz, 1H), 8.44 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.38 (d, J=5.2 Hz,1H), 2.44 (s, 3H).

Step g.

To a solution of 4-methyl-2-(4-nitro-1H-imidazol-1-yl) pyridine (2.4mmol) in MeOH (15 ml) was added 10% Pd/C (0.10% w/w) at rt. The reactionmixture was purged with H₂ gas for 2 h at rt. The resulting reactionmixture was carefully filtered through celite hyflow and concentratedunder reduced pressure to yield1-(4-methylpyridin-2-yl)-1H-imidazol-4-amine (2.4 mmol). MS: ES+ 175.1

Steps h-j.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 146 according to Scheme8 steps h, i and j. MS: ES+ 297.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76(s, 1H), 8.40 (d, J=1.53 Hz, 1H), 8.34 (d, J=5.19 Hz, 1H), 7.99 (d,J=1.53 Hz, 1H), 7.69 (s, 1H), 7.20 (d, J=4.88 Hz, 1H), 3.57-3.64 (m,1H), 3.38-3.52 (m, 3H), 3.24-3.27 (m, 1H), 2.41 (s, 3H), 2.10-2.21 (m,1H), 1.98-2.08 (m, 1H).

Example 175(S)-1-cyano-N-(1-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 174using 2-fluoro-6-methylpyridine in step d. MS: ES+ 297.0; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.76 (s, 1H), 8.40 (d, J=1.53 Hz, 1H), 7.99 (d,J=1.53 Hz, 1H), 7.86 (t, J=7.94 Hz, 1H), 7.60 (d, J=7.94 Hz, 1H), 7.22(d, J=7.63 Hz, 1H), 3.57-3.63 (m, 1H), 3.44-3.51 (m, 2H), 3.37-3.44 (m,1H), 3.23-3.27 (m, 1H), 2.51 (s, 3H), 2.10-2.20 (m, 1H), 1.98-2.08 (m,1H).

Example 176(S)-1-cyano-N-(1-(2-methylpyrimidin-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 174using 4-chloro-2-methylpyrimidine in step d. MS: ES+ 297.98; ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.87 (s, 1H), 8.77 (d, J=5.80 Hz, 1H), 8.60 (d,J=1.53 Hz, 1H), 8.06 (d, J=1.53 Hz, 1H), 7.77 (d, J=5.49 Hz, 1H),3.57-3.63 (m, 1H), 3.37-3.51 (m, 3H), 3.22-3.31 (m, 1H), 2.64 (s, 3H),2.11-2.20 (m, 1H), 1.99-2.08 (m, 1H).

Example 177(S)-1-cyano-N-(1-(4-cyanophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 174using 4-fluorobenzonitrile in step d. MS: ES+ 307.43; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.81 (s, 1H), 8.35 (d, J=1.83 Hz, 1H), 7.97-8.04 (m,2H), 7.88-7.93 (m, 2H), 7.87 (d, J=1.83 Hz, 1H), 3.58-3.62 (m, 1H),3.37-3.54 (m, 3H), 3.21-3.30 (m, 1H), 2.09-2.21 (m, 1H), 1.96-2.08 (m,1H).

Example 178(S)—N-(1-benzyl-2-methyl-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 174using 2-methyl-4(5)-nitroimidazole and benzyl chloride. MS: ES+ 310.47;¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.43 (s, 1H), 7.35-7.38 (m, 2H),7.27-7.31 (m, 1H), 7.17-7.18 (m, 2H), 7.14 (s, 1H), 5.09 (s, 2H),3.53-3.55 (m, 1H), 3.35-3.46 (m, 3H), 3.12-3.20 (m, 1H), 2.22 (s, 3H),2.06-2.13 (m, 1H), 1.91-1.99 (m, 1H).

Example 179(S)-1-cyano-N-(1-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 174using 4-(2-chloro-ethyl)-3,5-dimethyl-isoxazole. MS: ES+ 329.43; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.47 (s, 1H), 7.30 (s, 1H), 7.25 (s, 1H), 4.0(t, J=8.0 Hz, 2H), 3.55-3.59 (m, 1H), 3.38-3.46 (m, 3H), 3.15-3.22 (m,1H), 2.71 (t, J=6.8 Hz, 2H), 2.08-2.15 (m, 1H), 2.09 (s, 3H), 2.05 (s,3H), 1.97-2.02 (m, 1H).

Example 180(S)-1-cyano-N-(1-(3-cyanophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 8, Steps d,f,h,i,j)

Step f.

To a solution of 3-(4-nitro-1H-imidazol-1-yl) benzonitrile [preparedusing a procedure similar to that described for Example 174 using3-fluorobenzonitrile in step d] (0.65 mmol) in MeOH (8 ml) was added Zndust (1.96 mmol) and saturated solution of NH₄Cl (0.5 ml) at rt. Thereaction mixture was stirred at 60° C. for 1 h. The resulting reactionmixture was allowed to cool to rt and poured into water (50 ml) andextracted with EtOAc (2×50 ml). The combined organic phase was driedover Na₂SO₄, filtered and concentrated under reduced pressure yielding3-(4-amino-1H-imidazol-1-yl) benzonitrile (0.46 mmol). This material wasused immediately for the next step without further purification. MS: ES+185.29

Steps h-j.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 146 according to Scheme8 steps h, i and j. MS: ES+ 307.28; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.76 (s, 1H), 8.27 (m, 2H), 8.02 (dd, J=8.00 Hz, 1.2 Hz, 1H), 7.87 (d,J=1.53 Hz, 1H), 7.81 (d, J=7.94 Hz, 1H), 7.66-7.75 (m, 1H), 3.58-3.61(m, 1H), 3.44-3.50 (m, 2H), 3.38-3.40 (m, 1H), 3.23-3.29 (m, 1H),2.09-2.21 (m, 1H), 1.97-2.08 (m, 1H).

Example 181(S)-1-cyano-N-(1-(pyridin-3-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

(Prepared According to Scheme 8, Steps e,g,h,i,j)

Step e.

To a solution of 4-nitroimidazole (17.6 mmol), pyridine-3-boronic acid(35.3 mmol) and CuCl₂ in MeOH (40 ml) was added NaOH (35.3 mmol) at rtand the reaction mixture was stirred for 5 min. A slow stream of O₂ gaswas purged into the reaction mixture. The reaction mixture was heated at80° C. for 18 h whilst continuing the slow purging of O₂ gas throughoutthe reaction time. The resulting reaction mixture was allowed to cool tort and the purging of O₂ gas was removed. The reaction mixture was thenconcentrated under reduced pressure. The obtained crude material waspoured in to water (100 ml) and extracted with EtOAc (2×100 ml). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure yielding 3-(4-nitro-1H-imidazol-1-yl)pyridine(3.89 mmol). This material was directly used for the next step withoutfurther purification. MS: ES+ 191.1

Step g.

To a solution of 3-(4-nitro-1H-imidazol-1-yl)pyridine (3.68 mmol) inMeOH:THE (1:1, 10 ml) was added 10% Pd/C (0.25% w/w) at rt. The reactionmixture was purged with H₂ gas for 2 h at rt. The resulting reactionmixture was carefully filtered through celite hyflow and concentratedunder reduced pressure to yield 1-(pyridin-3-yl)-1H-imidazol-4-amine(3.12 mmol). This material was directly used for the next step withoutfurther purification.

Steps h-j.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 146 according to Scheme8 steps h, i and j. MS: ES+ 283.48; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.78 (s, 1H), 8.94 (d, J=2.78 Hz, 1H), 8.56 (dd, J=4.58, 1.22 Hz, 1H),8.24 (d, J=1.53 Hz, 1H), 8.09-8.12 (m, 1H), 7.81 (d, J=1.53 Hz, 1H),7.53-7.57 (m, 1H), 3.56-3.65 (m, 1H), 3.36-3.52 (m, 3H), 3.22-3.31 (m,1H), 2.11-2.19 (m, 1H), 1.99-2.07 (m, 1H).

Example 182(S)-1-cyano-N-(1-(pyridin-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 181using pyridine-4-boronic acid. MS: ES+ 283.43; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 10.83 (s, 1H), 8.63-8.65 (m, 2H), 8.45 (d, J=1.6 Hz, 1H), 7.91 (d,J=1.6 Hz, 1H), 7.75-7.77 (m, 2H), 3.59-3.63 (m, 1H), 3.42-3.51 (m, 2H),3.35-3.40 (m, 1H), 3.21-3.31 (m, 1H), 2.09-2.18 (m, 1H), 1.99-2.07 (m,1H).

Example 183(S)-1-cyano-N-(1-(3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 181using 3-methoxy-phenylboronic acid. MS: ES+ 312.43; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.73 (s, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.72 (d, J=1.6 Hz,1H), 7.38-7.43 (m, 1H), 7.17-7.19 (m, 2H), 6.92 (dd, J=6.0 Hz, 2.0 Hz,1H), 3.84 (s, 3H), 3.58-3.61 (m, 1H), 3.45-3.50 (m, 2H), 3.37-3.44 (m,1H), 3.21-3.28 (m, 1H), 2.07-2.16 (m, 1H), 1.98-2.05 (m, 1H).

Example 184(3S)—N-(1-(1-benzoylpiperidin-3-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide(Prepared According to Scheme 9)

Step b.

To a solution of 1,4-dinitro-1H-imidazole (15.82 mmol) [prepared using aprocedure described for Example 150 in step a] in MeOH:water (1:1, 40ml) was added 1-BOC-3-aminopiperidine (15.82 mmol) at rt. The reactionmixture was stirred at rt for 16 h. The resulting reaction mixture wassubjected to evaporation under reduced pressure in order to remove themajority of the MeOH. The obtained mixture was diluted with water (100ml) and extracted with EtOAc (2×60 ml). The combined organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography(60% EtOAc in hexane) yielding tert-butyl3-(4-nitro-1H-imidazol-1-yl)piperidine-1-carboxylate (9.12 mmol). MS:ES+ 297.43; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (d, J=1.2 Hz, 1H) 8.00(d, J=1.2 Hz, 1H), 4.26-4.33 (m, 1H), 4.00-4.05 (m, 1H), 3.71-3.76 (m,1H), 2.91-2.98 (m, 1H), 2.07-2.11 (m, 1H), 1.99-2.02 (m, 1H), 1.68-1.74(m, 1H), 1.44-1.50 (m, 2H), 1.40 (s, 9H).

Step c.

To a solution of tert-butyl3-(4-nitro-1H-imidazol-1-yl)piperidine-1-carboxylate (9.12 mmol) in DCM(30 ml) was added TFA (10 ml) at rt. The reaction mixture was stirred atrt for 10 min. The resulting reaction mixture was concentrated underreduced pressure. The obtained residue was azeotropically distilledusing DCM and further triturated with n-hexane to yield3-(4-nitro-1H-imidazol-1-yl)piperidine TFA salt (quantitative). Thismaterial was used directly for the next step without furtherpurification. MS: ES+ 197.10; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.35 (brs, 1H), 9.03 (br s, 1H), 8.61 (d, J=1.4 Hz, 1H), 8.01 (d, J=1.4 Hz, 1H),4.51-4.59 (m, 1H), 3.59-3.62 (m, 1H), 3.30-3.40 (m, 2H), 2.79-2.89 (m,1H), 2.15-2.18 (m, 1H), 1.95-2.08 (m, 2H), 1.69-1.80 (m, 1H).

Step i.

To a solution of benzoic acid (2.04 mmol) and TEA (3.07 mmol) in dry THF(5 ml) was added T3P (50% in EtOAc) (4.5 mmol) at rt. A solution of3-(4-nitro-1H-imidazol-1-yl)piperidine TFA salt (1.63 mmol) in THF (2ml) was added dropwise and the reaction mixture was stirred at rt for 16h. The reaction mixture was poured into water (200 ml), basified withsolid NaHCO₃ and extracted with EtOAc (2×100 ml). The combined organicphase was collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure yielding[3-(4-nitro-1H-imidazol-1-yl)piperidin-1-yl](phenyl)methanone(quantitative). This material was used directly for the next stepwithout further purification. MS: ES+ 301.38.

Step j.

To a solution of[3-(4-nitro-1H-imidazol-1-yl)piperidin-1-yl](phenyl)methanone (1.0 mmol)in MeOH (20 ml) was added 10% Pd/C (0.3 w/w) at rt. The reaction mixturewas purged with H₂ gas for 30 min at rt. The resulting reaction mixturewas carefully filtered through celite hyflow and concentrated underreduced pressure to yield[3-(4-amino-1H-imidazol-1-yl)piperidin-1-yl](phenyl)methanone(quantitative). This material was immediately used for the next stepwithout further purification.

Steps f-h.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 1 using(S)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid. MS: ES+393.19; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.58 (br s, 1H), 7.61 (br s,1H), 7.40-7.46 (m, 5H), 7.24 (br s, 1H), 4.35-4.47 (m, 1H), 4.22-4.27(m, 1H), 3.54-3.64 (m, 2H), 3.37-3.50 (m, 3H), 3.19-3.30 (m, 2H),2.89-2.98 (m, 1H), 1.90-2.2 (m, 4H), 1.45-1.75 (m, 2H).

Example 185(3S)—N-(1-(1-benzoylpyrrolidin-3-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide

Synthesized using a procedure similar to that described for Example 184using 1-BOC-3-aminopyrrolidine. MS: ES+ 379.58; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.58 (br s, 1H), 7.62 (s, 1H), 7.43-7.54 (m, 5H), 7.28(s, 1H), 4.88-4.93 (m, 1H), 4.79-4.83 (m, 1H), 3.95-3.99 (m, 1H),3.84-3.89 (m, 1H), 3.69-3.72 (m, 1H), 3.52-3.62 (m, 3H), 3.42-3.46 (m,2H), 3.17-3.22 (m, 2H), 2.13-2.16 (m, 1H), 2.07-2.10 (m, 1H).

Example 186(3S)—N-(1-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide(Prepared According to Scheme 9)

Step d.

To a solution of 3-(4-nitro-1H-imidazol-1-yl)piperidine TFA salt(prepared in Example 184) (2.25 mmol) and K₂CO₃ (6.77 mmol) in THF (8ml) was added benzyl bromide (1.8 mmol) at rt. The reaction mixture washeated to 80° C. for 16 h. The resulting reaction mixture was pouredinto water (70 ml) and extracted with EtOAc (2×50 ml). The combinedorganic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield1-benzyl-3-(4-nitro-1H-imidazol-1-yl)piperidine (quantitative). Thismaterial was directly used for the next step without furtherpurification. MS: ES+ 287.43.

Step e.

A solution of 1-benzyl-3-(4-nitro-1H-imidazol-1-yl)piperidine (1.39mmol) in THF:water (1:1, 10 ml) was stirred at rt for 5 min. Fe power(13.98 mmol) and NH₄Cl (13.98 mmol) were added and the reaction mixturewas heated at 80° C. for 0.5 h. The resulting reaction mixture wasallowed to cool to rt and filtered through celite hyflow. The filtratewas poured into water (20 ml) and extracted with EtOAc (2×5 ml). Thecombined organic phase was dried over Na₂SO₄, filtered and the resultingsolution was immediately used for the next step without evaporation.

Steps f-h.

The title compound was synthesised from the previous intermediate usinga procedure similar to that described for Example 1 using(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid. MS: ES+379.24; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.50 (s, 1H), 7.55 (s, 1H),7.24-7.33 (m, 6H), 4.15-4.25 (m, 1H), 3.52-3.57 (m, 3H), 3.38-3.50 (m,2H), 3.16-3.22 (m, 1H), 2.86-2.89 (m, 1H), 2.66-2.73 (m, 1H), 2.25-2.35(m, 1H), 2.11-2.17 (m, 2H), 1.93-2.07 (m, 2H), 1.60-1.68 (m, 2H),1.54-1.57 (m, 2H).

Example 187(3S)-1-cyano-N-(1-(1-methylpiperidin-3-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 9)

Step k.

To a solution of 3-(4-nitro-1H-imidazol-1-yl)piperidine TFA salt(prepared in Example 184) (2.58 mmol) and 37% aqueous formaldehydesolution (10 ml) in MeOH (20 ml) was added sodium cyanoborohydride (3.87mmol) at rt. Acetic acid (6.19 mmol) was added dropwise to the reactionmixture and stirred at rt for 16 h. The resulting reaction mixture wasconcentrated under reduced pressure. The obtained residue was pouredinto water (100 ml), basified with solid NaHCO₃ and extracted with EtOAc(2×100 ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield1-methyl-3-(4-nitro-1H-imidazol-1-yl)piperidine (quantitative). MS: ES+211.04; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.56 (s, 1H), 8.01 (s, 1H),4.33-4.40 (m, 1H), 2.86-2.89 (m, 1H), 2.51-2.57 (m, 1H), 2.20-2.36 (m,1H), 2.22 (s, 3H), 2.05-2.10 (m, 1H), 1.95-1.99 (m, 1H), 1.67-1.79 (m,2H), 1.54-1.60 (m, 1H).

Step j.

To a solution of 1-methyl-3-(4-nitro-1H-imidazol-1-yl)piperidine (1.90mmol) in MeOH (50 ml) was added 10% Pd/C (0.25 w/w) at rt. The reactionmixture was purged with H₂ gas at rt for 0.5 h. The resulting reactionmixture was carefully filtered through celite hyflow and concentratedunder reduced pressure to yield1-(1-methylpiperidin-3-yl)-1H-imidazol-4-amine (quantitative). Thismaterial was immediately used for the next step without furtherpurification. MS: ES+ 378.98; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.46 (brs, 1H), 7.56 (s, 1H), 7.29 (s, 1H), 4.10-4.21 (m, 1H), 3.40-3.52 (m,2H), 3.18-3.38 (m, 4H), 3.07-3.19 (m, 1H), 2.80-2.91 (m, 1H), 2.59-2.68(m, 1H), 2.20 (S, 3H), 2.08-2.18 (m, 2H), 1.87-1.90 (m, 2H), 1.51-1.73(m, 2H), 1.39 (s, 9H).

Steps f-h.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 1 using(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid. MS: ES+303.04; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.58 (br s, 1H), 7.58 (s, 1H),7.37 (s, 1H), 4.57-4.62 (m, 1H), 3.51-3.60 (m, 1H), 3.34-3.50 (m, 4H),3.20-3.26 (m, 2H), 3.01-3.14 (m, 2H), 2.50 (s, 3H), 2.07-2.17 (m, 2H),1.95-2.07 (m, 2H), 1.70-1.80 (m, 2H).

Example 188(3S)-1-cyano-N-(1-(1-methylpyrrolidin-3-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 187using 1-BOC-3-aminopyrrolidine. MS: ES+ 289.18; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.52 (s, 1H), 7.50 (s, 1H), 7.33 (s, 1H), 4.71-4.82 (m,1H), 3.54-3.58 (m, 1H), 3.42-3.46 (m, 2H), 3.17-3.22 (m, 1H), 2.87-2.88(m, 1H), 2.67-2.70 (m, 1H), 2.52-2.61 (m, 1H), 2.33-2.41 (m, 2H), 2.28(s, 3H), 2.23-2.26 (m, 1H), 2.06-2.12 (m, 1H), 1.96-2.02 (m, 1H),1.82-1.84 (m, 1H).

Example 189(S)—N-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide(Prepared According to Scheme 10)

Step a.

To a solution of Intermediate 14 (0.7 mmol) in DCM (2 ml) was added TEA(1.42 mmol) and acetyl chloride (0.85 mmol) at 0° C. The reactionmixture was stirred at rt for 1 h. The resulting reaction mixture waspoured into ice cold water (30 ml) and extracted with DCM (3×30 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (2% MeOH in DCM) yielding the tert-butyl(S)-3-((5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.55 mmol). MS: ES+ 395.60.

Step f.

4M HCl in 1,4-dioxane (5 ml) was added to tert-butyl(S)-3-((5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate (0.55 mmol) and stirred at rt for 1 h. Theresulting reaction mixture was concentrated under reduced pressure. Theobtained residue was neutralized by aqueous solution of saturatedNaHCO₃. The resulting mixture was extracted with DCM (3×100 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The obtained residue was trituratedwith diethyl ether (10 ml) yielding(S)—N-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide (0.49 mmol). The material was used directlyfor the next step without further purification. MS: ES+ 295.28.

Step g.

To a solution of(S)—N-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide (0.5 mmol) in CHCl₃ (5 ml) was added DIPEA(1.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15min. Cyanogen bromide (0.7 mmol) was added and the reaction mixture wasstirred at 0° C. for 30 min. The resulting reaction mixture was pouredinto ice cold water (50 ml) and extracted with DCM (2×30 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (2% MeOH in DCM) The material obtained afterchromatography was further triturated with diethyl ether (5 ml) yieldingthe title compound (0.13 mmol). MS: ES+ 320.3; ¹H NMR (run at 80° C.,400 MHz, DMSO-d₆) δ ppm 11.99 (br s, 1H), 4.62 (s, 2H), 3.72-3.85 (m,2H), 3.60-3.65 (m, 1H), 3.49-3.56 (m, 1H), 3.38-3.48 (m, 2H), 3.28-3.37(m, 1H), 2.60-2.80 (m, 2H), 2.16-2.28 (m, 1H), 2.05-2.10 (m, 4H).

Example 190(S)-1-cyano-N-(5-isobutyryl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 189using 2-methylpropanoyl chloride. MS: ES+ 348.48; ¹H NMR (run at 80° C.,400 MHz, DMSO-d₆) δ ppm 12.00 (br s, 1H), 4.65 (s, 2H), 3.79-3.82 (m,2H), 3.60-3.64 (m, 1H), 3.51-3.54 (m, 1H), 3.40-3.45 (m, 2H), 3.33-3.38(m, 1H), 2.95-2.98 (m, 1H), 2.67-2.72 (m, 2H), 2.16-2.23 (m, 1H),2.05-2.12 (m, 1H), 1.04 (d, J=6.40 Hz, 6H).

Example 191(S)—N-(5-benzoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 189using benzoyl chloride. MS: ES+ 382.38; ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.27 (br s, 1H), 7.41-7.62 (m, 5H), 4.76 (s, 2H), 3.92-3.94 (m, 1H),3.34-3.61 (m, 6H), 2.66-2.73 (m, 2H), 2.21-2.28 (m, 1H), 2.04-2.11 (m,1H).

Example 192(S)-1-cyano-N-(5-(2-methoxybenzoyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 189using 2-methoxybenzoyl chloride. MS: ES+ 412.43; ¹H NMR (run at 80° C.,400 MHz, DMSO-d₆) δ ppm 12.03 (br s, 1H), 7.42 (t, J=7.6 Hz, 1H),7.11-7.23 (m, 2H), 7.01-7.04 (m, 1H), 4.78 (s, 2H), 4.29-4.39 (m, 1H),3.94-4.08 (m, 1H), 3.81 (s, 3H), 3.60-3.62 (m, 1H), 3.38-3.47 (m, 3H),3.31-3.36 (m, 1H), 2.73-2.79 (m, 1H), 2.58-2.65 (m, 1H), 2.19-2.22 (m,1H), 2.06-2.11 (m, 1H).

Example 193(5)-1-cyano-N-(5-picolinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 10)

Step b.

To a solution of 2-pyridine carboxylic acid (0.406 mmol) in THF (2 ml)was added T3P (50% in EtOAc) (13.95 mmol) at rt. The reaction mixturewas stirred at rt for 15 min. Intermediate 14 (0.41 mmol) and DIPEA(1.23 mmol) were added to the reaction mixture. The reaction mixture wasstirred at rt for 1 h. The resulting reaction mixture was poured intowater (50 ml) and extracted with EtOAc (3×50 ml). The combined organicphase was collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by flashchromatography (4% MeOH in DCM) yielding tert-butyl(S)-3-((5-picolinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl) pyrrolidine-1-carboxylate (0.32 mmol). MS: ES+ 458.66.

Step f.

To a solution of tert-butyl(S)-3-((5-picolinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.32 mmol) in DCM (4 ml) was added TFA (1.31 mmol) at 0° C. Thereaction mixture was stirred at rt for 2 h. The resulting reactionmixture was concentrated under reduced pressure. The obtained residuewas neutralized by aqueous solution of saturated NaHCO₃ and extractedwith DCM (3×50 ml). The combined organic phase was collected, dried overNa₂SO₄, filtered and concentrated under reduced pressure yielding(S)—N-(5-picolinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide (0.31 mmol). This material was directly usedfor the next step without further purification. MS: ES+ 358.43.

Step g.

To a solution of(S)—N-(5-picolinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide (0.31 mmol) in THF (6 ml) was added K₂CO₃(0.92 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30min. Cyanogen bromide (0.46 mmol) was added and the reaction mixture wasthen stirred at rt for 30 min. The resulting reaction mixture was pouredinto ice-water (100 ml) extracted with EtOAc (3×50 ml). The combinedorganic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (4% MeOH in DCM) yielding the title compound(0.14 mmol). MS: ES+ 383.63; ¹H NMR (run at 80° C., 400 MHz, DMSO-d₆) δppm 11.99 (br s, 1H), 8.62 (d, J=4.58 Hz, 1H), 7.94 (t, J=7.48 Hz, 1H),7.62 (d, J=7.33 Hz, 1H), 7.49-7.52 (m, 1H), 4.80 (s, 2H), 3.97-4.07 (m,1H), 3.88-3.94 (m, 1H), 3.60-3.65 (m, 1H), 3.47-3.53 (m, 1H), 3.37-3.45(m, 2H), 3.31-3.35 (m, 1H), 2.71-2.81 (m, 2H), 2.15-2.22 (m, 1H),2.04-2.13 (m, 1H).

Example 194(S)-1-cyano-N-(5-(1-methyl-1H-pyrazole-3-carbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 193using 1-methyl-1H-pyrazole-3-carboxylic acid. MS: ES+ 386.43; ¹H NMR(run at 80° C., 400 MHz, DMSO-d₆) δ ppm 11.98 (br s, 1H), 7.74 (s, 1H),6.57 (s, 1H), 4.89 (s, 2H), 4.06-4.19 (m, 2H), 3.93 (s, 3H), 3.60-3.64(m, 1H), 3.51-3.55 (m, 1H), 3.43-3.49 (m, 2H), 3.31-3.37 (m, 1H),2.74-2.77 (m, 2H), 2.19-2.25 (m, 1H), 2.04-2.11 (m, 1H).

Example 195(S)-1-cyano-N-(5-(5-(1-ethyl-2-oxo-1,2-dihydropyridine-3-carbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 193using 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid. MS: ES+413.15; ¹H NMR (run at 80° C., 400 MHz, DMSO-d₆) δ ppm 11.99 (br s, 1H),7.78 (dd, J=6.71, 2.14 Hz, 1H), 7.47-7.49 (m, 1H), 6.28 (t, J=6.714 Hz,1H), 4.71 (s, 2H), 3.72-3.79 (m, 1H), 3.60-3.67 (m, 1H), 3.50-3.54 (m,2H), 3.47 (s, 3H), 3.38-3.45 (m, 2H), 3.29-3.36 (m, 1H), 2.70-2.73 (m,2H), 2.17-2.23 (m, 1H), 2.07-2.13 (m, 1H).

Example 196(S)-1-cyano-N-(5-nicotinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 193using nicotinic acid. MS: ES+ 383.20; ¹H NMR (run at 80° C., 400 MHz,DMSO-d₆) δ ppm 12.00 (br s, 1H), 8.66-8.69 (m, 2H), 7.87 (d, J=8.0 Hz,1H), 7.48-7.51 (m, 1H), 4.72 (s, 2H), 3.73-3.89 (m, 1H), 3.60-3.65 (m,1H), 3.51-3.55 (m, 2H), 3.41-3.48 (m, 2H), 3.31-3.37 (m, 1H), 2.75-2.77(m, 2H), 2.19-2.25 (m, 1H), 2.04-2.11 (m, 1H).

Example 197(S)-1-cyano-N-(5-(dimethylglycyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 193using N,N-dimethylglycine. MS: ES+ 363.23; ¹H NMR (400 MHz, CD₃OD) δ ppm4.72-4.77 (m, 2H), 3.86-3.98 (m, 2H), 3.61-3.65 (m, 2H), 3.51-3.62 (m,2H), 3.32-3.42 (m, 2H), 2.72-2.84 (m, 2H), 2.38 (s, 3H), 2.32 (s, 3H),2.15-2.30 (m, 3H).

Example 198 methyl(S)-2-(1-cyanopyrrolidine-3-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

Synthesised using a procedure similar to that described for Example 189using methyl chloroformate. MS: ES+ 336.43; ¹H NMR (400 MHz, DMSO-d₆) δppm 12.24 (br s, 1H), 4.55 (s, 2H), 3.67-3.70 (m, 2H), 3.64 (s, 3H),3.59-3.61 (m, 1H), 3.48-3.53 (m, 1H), 3.38-3.46 (m, 2H), 3.28-3.32 (m,1H), 2.65-2.68 (m, 2H), 2.08-2.20 (m, 1H), 2.01-2.08 (m, 1H).

Example 199 2-methoxyethyl(S)-2-(1-cyanopyrrolidine-3-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

Synthesised using a procedure similar to that described for Example 189using 2-methoxyethyl chloroformate. MS: ES+ 380.38; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.24 (s, 1H), 4.55 (s, 2H), 4.15-4.17 (m, 2H), 3.68-3.70(m, 2H), 3.59-3.63 (m, 1H), 3.51-3.54 (m, 2H), 3.38-3.45 (m, 3H),3.29-3.31 (m, 1H), 3.26 (s, 3H), 2.65-2.67 (m, 2H), 2.14-2.22 (m, 1H),1.99-2.08 (m, 1H).

Example 200(S)-1-cyano-N-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 10)

Step d.

To a solution of Intermediate 14 (0.56 mmol) in MeOH (5 ml) were added37% aq formaldehyde (1.70 mmol) and acetic acid (3 drops) at 0° C. Thereaction mixture was stirred at 0° C. for 30 min, NaCNBH₃ (1.12 mmol)was added to the reaction mixture at 0° C. The reaction mixture wasstirred at rt for 3 h. The resulting reaction mixture was poured in toice water (10 ml) and extracted with DCM (3×25 ml). The combined organicphase was collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by flashchromatography (3% MeOH in DCM) yielding tert-butyl(S)-3-((5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate (0.35 mmol). MS: ES+ 367.3.

Step f.

To a solution of tert-butyl(S)-3-((5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.35 mmol) in DCM (10 ml) was added TFA (1.4 mmol) at 0° C. Thereaction mixture was stirred at rt for 3 h. The resulting reactionmixture was concentrated under reduced pressure. The obtained residuewas triturated with diethyl ether (10 ml) yielding(S)—N-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamideTFA salt (0.21 mmol). The material was used directly for the next stepwithout further purification. MS: ES+ 267.0.

Step g.

To a solution of(S)—N-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamideTFA salt (0.21 mmol) in DCM (2 ml) was added TEA (0.63 mmol) at 0° C.The reaction mixture was stirred at 0° C. for 10 min. Cyanogen bromide(0.24 mmol) was added to the reaction mixture at 0° C. The reactionmixture was stirred at 0° C. for 30 min. The resulting reaction mixturewas poured into ice water (10 ml) and extracted with DCM (3×25 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (5% MeOH in DCM) to yield the title compound(0.07 mmol). MS: ES+ 292.08; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.20 (brs, 1H), 3.55-3.68 (m, 3H), 3.48-3.54 (m, 1H), 3.39-3.47 (m, 2H),3.25-3.31 (m, 1H), 2.79 (m, 2H), 2.68 (m, 2H), 243 (s, 3H), 216-220 (m,1H), 200-208 (m, 1H)

Example 201(S)—N-(5-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide(Prepared According to Scheme 10)

Step e.

To a solution of Intermediate 14 (0.85 mmol) in MeOH (5 ml) was addedbenzaldehyde (1.70 mmol) and acetic acid (3 drops) at 0° C. The reactionmixture was stirred at 0° C. for 30 min. NaCNBH₃ (1.70 mmol) was addedto the reaction mixture at 0° C. The reaction mixture was stirred at rtfor 3 h. The resulting reaction mixture was poured into ice water (10ml) and extracted with DCM (3×25 ml). The combined organic phase wasdried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography (2% MeOH in DCM)yielding tert-butyl(S)-3-((5-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.58 mmol). MS: ES+ 443.4.

Steps f-g.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 200 according to Scheme8 steps d and e. MS: ES+ 368.38; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.16(br s, 1H), 7.34-7.46 (m, 4H), 7.24-7.31 (m, 1H), 3.69 (s, 2H),3.47-3.65 (m, 4H), 3.37-3.43 (m, 2H), 3.25-3.33 (m, 1H), 2.73-2.79 (m,2H), 2.63-2.67 (m, 2H), 2.13-2.22 (m, 1H), 1.99-2.07 (m, 1H).

Example 202(S)-1-cyano-N-(5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 10)

Step c.

To a solution of Intermediate 14 (0.56 mmol) in DCM (2 ml) was added TEA(1.13 mmol) and methanesulfonyl chloride (0.84 mmol) at 0° C. Thereaction mixture was stirred at rt for 1 h. The resulting reactionmixture was poured into ice water (10 ml) and extracted with DCM (3×20ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (2% MeOH in DCM) yieldingtert-butyl(S)-3-((5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)-pyrrolidine-1-carboxylate(0.43 mmol). MS: ES+ 431.38.

Step f.

4M HCl in 1,4-dioxane (4 mmol) was added to tert-butyl(S)-3-((5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate (0.43 mmol) at rt. The reaction mixture wasstirred at rt for 1 h. The resulting reaction mixture was concentratedunder reduced pressure. The obtained residue was triturated with diethylether (10 ml) yielding(S)—N-(5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamidehydrochloride (0.36 mmol). The material was used directly for the nextstep without further purification. MS: ES+ 331.28.

Step g.

To a solution of(S)—N-(5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamidehydrochloride (0.35 mmol) in CHCl₃ (4 ml) was added DIPEA (1.1 mmol) at0° C. The reaction mixture was stirred at 0° C. for 10 min. Cyanogenbromide (0.53 mmol) was added and the reaction mixture was stirred at 0°C. for 30 min. The resulting reaction mixture was poured into ice-water(10 ml) and extracted with DCM (3×25 ml). The organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography (2%MeOH in DCM) yielding the title compound (0.26 mmol). MS: ES+ 356.39; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.28 (s, 1H), 4.40 (s, 2H), 3.59-3.64 (m,1H), 3.47-3.55 (m, 3H), 3.38-3.47 (m, 2H), 3.26-3.33 (m, 1H), 2.96 (s,3H), 2.75-2.78 (m, 2H), 2.14-2.23 (m, 1H), 2.00-2.10 (m, 1H).

Example 203(S)-1-cyano-N-(5-(isopropylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 202using isopropylsulfonyl chloride. MS: ES+ 384.28; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.26 (s, 1H), 4.47 (s, 2H), 3.59-3.63 (m, 3H), 3.44-3.53(m, 1H), 3.37-3.42 (m, 3H), 3.26-3.31 (m, 1H), 2.67-2.71 (m, 2H),2.14-2.17 (m, 1H), 2.00-2.08 (m, 1H), 1.22 (d, J=6.4 Hz, 6H).

Example 204(S)-1-cyano-N-(5-(phenylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 202using benzenesulfonyl chloride. MS: ES+ 418.58; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.22 (br s, 1H), 7.81-7.83 (m, 2H), 7.68-7.72 (m, 1H),7.59-7.63 (m, 2H), 4.31 (s, 2H), 3.60-3.62 (m, 1H), 3.47-3.52 (m, 1H),3.35-3.45 (m, 4H), 3.24-3.29 (m, 1H), 2.61-2.67 (m, 2H), 2.12-2.21 (m,1H), 1.98-2.07 (m, 1H).

Example 205 (S)-1-cyano-N-(5-(4-ethynylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide (Prepared According to Scheme 11)

Step a.

To a solution of 2-(4-bromophenyl)ethan-1-ol (4.97 mmol) in DCM (13 ml)was added Dess-Martin periodinane (6.2 mmol) at 0° C. The reactionmixture was stirred at rt for 16 h. The reaction mixture was partiallyevaporated and the obtained residue was filtered through celite hyflow.The filtrate was concentrated under reduced pressure. The resultingresidue was purified by flash chromatography (9-10% EtOAc in hexane)yielding 2-(4-bromophenyl) acetaldehyde (3.51 mmol). MS: ES− 197.10; ¹HNMR (400 MHz, DMSO-d⁶) δ ppm 9.68 (s, 1H), 7.54 (d, J=2.0 Hz, 2H), 7.21(d, J=8.4 Hz, 2H), 3.79 (d, J=0.8 Hz, 2H).

Step b.

Bromine (3.5 mmol) was added dropwise to a solution of 2-(4-bromophenyl)acetaldehyde (3.5 mmol) in DCM (13 ml) at 0° C. The reaction mixture wasstirred at rt for 2 h. The resulting reaction mixture was then pouredinto saturated NaHCO₃ solution (20 ml) and extracted with DCM (2×40 ml).The combined organic phase was collected, dried over Na₂SO₄, filteredand concentrated under reduced pressure yielding2-bromo-2-(4-bromophenyl)acetaldehyde. The obtained material was usedimmediately for the next step without any further processing.

Step c.

Thiourea (7.0 mmol) was added to a solution of 2-bromo-2-(4-bromophenyl)acetaldehyde in EtOH (8 ml) at rt. The reaction mixture was heated at90° C. for 6 h. The resulting reaction mixture was allowed to cool to rtand was evaporated under reduced pressure. The obtained residue waspartitioned between saturated NaHCO₃ (20 ml) and DCM (30 ml). Theorganic layer was separated and the aqueous layer was further extractedwith DCM (2×30 ml). The combined organic phase was collected, dried overNa₂SO₄, filtered and concentrated under reduced pressure yielding5-(4-bromophenyl) thiazol-2-amine (2.37 mmol). MS: ES+ 255.1, 257.08; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.49-7.52 (m, 2H), 7.46 (s, 1H), 7.36-7.38(m, 2H), 7.23 (br s, 2H)

Step d.

To a solution of (3S)-BOC-1-pyrrolidine-3-carboxylic acid (0.78 mmol) inTHF (2 ml) was added T3P (50% in EtOAc) (1.17 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 15 min. 5-(4-bromophenyl)thiazol-2-amine (0.78 mmol) and TEA (2.3 mmol) were then added to thereaction mixture. The reaction mixture was stirred at rt for 1 h. Theresulting reaction mixture was poured into water (50 ml) and extractedwith EtOAc (3×30 ml). The combined organic phase was collected, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography (1-2% MeOH inDCM) yielding tert-butyl(S)-3-((5-(4-bromophenyl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.37 mmol). MS: ES+ 452.34, 454.28

Step e.

Tert-butyl(S)-3-((5-(4-bromophenyl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.88 mmol), Pd(PPh₃)₂Cl₂ (0.13 mml) and CuI (0.05 mmol) were mixed inan oven dried glass tube under nitrogen atmosphere. The glass tube wasslowly flushed with nitrogen and immediately sealed. Trimethylsilylacetylene (4.42 mmol) and DIPEA (10 ml) were added to reaction mixturevia syringe. A slow stream of nitrogen was again passed in the sealedtube. The tightly sealed glass tube was then subjected to heating at110° C. (external temperature) for 16 h. The resulting reaction mixturewas poured into water (30 ml) and extracted with EtOAc (2×50 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (30-40% EtOAc in hexane) yielding tert-butyl(S)-3-((5-(4-((trimethylsilyl)ethynyl)phenyl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.63 mmol). MS: ES+ 470.53

Step f.

A solution of tert-butyl(S)-3-((5-(4-((trimethylsilyl)ethynyl)phenyl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.63 mmol) in MeOH (10 ml) was stirred at 0° C. for 5 min. 5M aqueousKOH solution (7 ml) was added to the reaction mixture at 0° C. Thereaction mixture was stirred at rt for 30 min. The resulting reactionmixture was poured into water (40 ml) and extracted with EtOAc (2×50ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (60-70% EtOAc in hexane) yieldingtert-butyl (S)-3-((5-(4-ethynylphenyl) thiazol-2-yl) carbamoyl)pyrrolidine-1-carboxylate (0.1 mmol).

This material was used directly for the next step without furtherprocessing.

Step g.

To a solution of tert-butyl (S)-3-((5-(4-ethynylphenyl) thiazol-2-yl)carbamoyl) pyrrolidine-1-carboxylate (0.08 mmol) in DCM (2 ml) was addedTFA (0.3 ml) at 0° C. The reaction mixture was stirred at rt for 2 h.The resulting reaction mixture was concentrated under reduced pressure.The obtained residue was triturated with diethyl ether (5 ml) yielding(S)—N-(5-(4-ethynylphenyl) thiazol-2-yl)pyrrolidine-3-carboxamide TFAsalt (0.067 mmol). The material was used directly for the next stepwithout further purification. MS: ES+ 298.38.

Step h.

To a solution of (S)—N-(5-(4-ethynylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide TFA salt (0.12 mmol) in DCM (2ml) was added K₂CO₃ (0.36 mmol) at rt and stirred for 15 min. Cyanogenbromide (0.14 mmol) was added to the reaction mixture at 0° C. Thereaction mixture was then stirred at rt for 1 h. The resulting reactionmixture was poured into water (20 ml) and extracted with EtOAc (2×20ml). The combined organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (1.5-2.5% MeOH in DCM) yielding the titlecompound (0.01 mmol). MS: ES+ 322.96; ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.49 (s, 1H), 7.99 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz,2H), 4.29 (s, 1H), 3.61-3.66 (m, 1H), 3.53-3.58 (m, 1H), 3.40-3.48 (m,3H), 2.16-2.23 (m, 1H), 2.06-2.10 (m, 1H).

Example 206(S)-1-cyano-N-(5-(3-ethynylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 205using 3-bromophenethyl alcohol in step a. MS: ES+ 323.06; ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 7.99 (s, 1H), 7.61-7.66 (m, 2H),7.49-7.53 (m, 1H), 7.39-7.46 (m, 1H), 4.29 (s, 1H), 3.61-3.67 (m, 1H),3.53-3.59 (m, 1H), 3.42-3.50 (m, 2H), 3.36-3.42 (m, 1H), 2.16-2.26 (m,1H), 2.08-2.12 (m, 1H).

Example 207(3S)-1-cyano-N-(5-(N-(1-phenylethyl)sulfamoyl)pyridin-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 12)

Step a.

Chlorosulfonic acid (89.2 mmol) was slowly added to 2-aminopyridine(10.6 mmol) under nitrogen atmosphere at 0° C. Upon completion ofaddition the reaction mixture was allowed to warm to rt and was thenheated at 150° C. for 2 h. The resulting reaction mixture was allowed tocool to rt, poured into ice cold water (100 ml) and neutralized byportion-wise addition of solid NaHCO₃. The resulting suspension wasextracted with EtOAc (2×50 ml). The combined organic phase was driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theobtained crude material was crystallized from diethyl ether: heptaneyielding 6-aminopyridine-3-sulfonyl chloride (5.75 mmol). MS: ES+193.19; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.71 (d, J=2.75 Hz, 1H), 7.98 (dd,J=9.00, 2.59 Hz, 1H), 6.59 (dd, J=9.16, 0.61 Hz, 1H), 5.41 (br s, 2H).

Step b.

To a solution of 1-phenylethan-1-amine (2.08 mmol) in THF (5 ml) wasadded TEA (2.5 mmol) at 0° C. and the reaction mixture was stirred for 5min at 0° C. 6-Aminopyridine-3-sulfonyl chloride (2.08 mmol) was addedto the reaction mixture at 0° C. and was then stirred at rt for 30 min.The resulting reaction mixture was poured into water (50 ml) andextracted with EtOAc (2×30 ml). The combined organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by column chromatography(25% EtOAc in hexane) yielding6-amino-N-(1-phenylethyl)pyridine-3-sulfonamide (1.62 mmol). MS: ES+278.33; ¹H NMR (400 MHz, DMSO₆) δ ppm 8.12 (dd, J=2.44, 0.61 Hz, 1H),7.94 (d, J=8.24 Hz, 1H), 7.49 (dd, J=8.85, 2.44 Hz, 1H), 7.18-7.25 (m,4H), 7.13-7.17 (m, 1H), 6.75 (br s, 2H), 6.35 (dd, J=8.85, 0.61 Hz, 1H),4.25-4.30 (m, 1H), 1.22 (d, J=7.02 Hz, 3H).

Step c.

A mixture of anhydrous DCM (5 ml) and anhydrous DMF (1.39 mmol) wastaken in a glass tube under nitrogen atmosphere at 0° C. Oxalyl chloride(1.39 mmol) was added to the reaction mixture under nitrogen atmosphereat 0° C. Anhydrous pyridine (1.39 mmol) was added to the reactionmixture under nitrogen atmosphere at 0° C. A solution of(S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (1.39 mmol) inDCM (5 ml) was added dropwise to the reaction mixture under nitrogenatmosphere at 0° C. The resulting reaction mixture was stirred undernitrogen atmosphere at rt for 1 h which resulted in formation of thedesired acid chloride. Simultaneously a solution of6-amino-N-(1-phenylethyl)pyridine-3-sulfonamide in DMF (3 ml) wasprepared in another glass tube under nitrogen atmosphere. TEA (1.65mmol) was added to the reaction mixture in the second glass tube undernitrogen atmosphere at 0° C. Thereafter the acid chloride solution fromthe first glass tube was carefully collected in a syringe and was addeddropwise to the reaction mixture in the second glass tube under nitrogenatmosphere at 0° C. The final reaction mixture was stirred at rt for 16h. The resulting reaction mixture was concentrated under reducedpressure and the obtained crude material was azeotropically distilledusing DCM (2×50 ml). The resulting residue was purified by columnchromatography (4% MeOH in DCM) yielding tert-butyl(3S)-3-((5-(N-(1-phenylethyl)-sulfamoyl)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.46 mmol). MS: ES+ 475.71

Step d.

To a solution of tert-butyl(3S)-3-((5-(N-(1-phenylethyl)sulfamoyl)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.46 mmol) in DCM (3 ml) was added TFA (2.5 ml) at 0° C. The reactionmixture was stirred at rt for 15 min. The resulting reaction mixture wasconcentrated under reduced pressure. The obtained residue wasazeotropically distilled using DCM (2×15 ml) yielding(3S)—N-(5-(N-(1-phenylethyl)sulfamoyl)pyridin-2-yl)pyrrolidine-3-carboxamideTFA salt (0.37 mmol). This material was used directly for the next stepwithout further purification.

Step e.

To a solution of(3S)—N-(5-(N-(1-phenylethyl)sulfamoyl)pyridin-2-yl)pyrrolidine-3-carboxamideTFA salt (0.37 mmol) in THF (3 ml) was added TEA (1.49 mmol) at 0° C.The reaction mixture was stirred at 0° C. for 5 min. Cyanogen bromide(0.44 mmol) was added to the reaction mixture at 0° C. The reactionmixture was then stirred at rt for 30 min. The resulting reactionmixture was poured into water (30 ml) and extracted with EtOAc (2×20ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (10% MeOH in DCM) yielding thetitle compound (0.04 mmol). MS: ES+ 399.93; ¹H NMR (400 MHz, DMSO₆) δppm 11.07 (br s, 1H), 8.43-8.45 (m, 1H), 8.33-8.35 (m, 1H), 8.07-8.09(m, 1H), 7.93-7.97 (m, 1H), 7.09-7.21 (m, 5H), 4.35-4.47 (m, 1H),3.56-3.63 (m, 1H), 3.35-3.53 (m, 4H), 2.14-2.20 (m, 1H), 2.06-2.12 (m,1H), 1.25-1.27 (m, 3H).

Example 208(3S)-1-cyano-N-(5-(N-methyl-N-(1-phenylethyl)sulfamoyl)pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 207using methyl(1-phenylethyl)amine in step b. MS: ES+ 414.68; ¹H NMR (400MHz, CD₃OD) δ ppm 8.72-8.73 (m, 1H), 8.33-8.35 (m, 1H), 8.16-8.19 (m,1H), 7.24-7.37 (m, 5H), 5.29-5.32 (m, 1H), 3.69-3.71 (m, 2H), 3.51-3.60(m, 2H), 3.32-3.39 (m, 1H), 2.65 (s, 3H), 2.21-2.32 (m, 2H), 1.38-1.40(m, 3H).

Example 209(S)-1-cyano-N-(6-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 13)

Step a.

To a solution of (3S)-BOC-1-pyrrolidine-3-carboxylic acid (4.65 mmol) inTHF (20 ml) was added T3P (50% in EtOAc) (13.95 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 15 min.6-Bromoimidazo[1,2-a]pyridin-2-amine (4.65 mmol) and DIPEA (13.95 mmol)were added to the reaction mixture at 0° C. The reaction mixture wasstirred at rt for 1 h. The resulting reaction mixture was poured intowater (50 ml) and extracted with EtOAc (3×100 ml). The combined organicphase was collected, dried over Na₂SO₄, filtered and concentrated underreduced pressure yielding tert-butyl(S)-3-((6-bromoimidazo[1,2-a]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(3.80 mmol). This material was used directly for the next step withoutfurther purification. MS: ES+ 409.50, 411.50.

Step b.

A solution of tert-butyl(S)-3-((6-bromoimidazo[1,2-a]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(2.45 mmol) was prepared in DMF (20 ml) in a glass tube. Zn(CN)₂ (7.35mmol) and TEA (4.90 mmol) were added to the reaction mixture at rt undernitrogen atmosphere. The reaction mixture was purged with nitrogen gasat rt for 15 min. Pd(dba)₂ (0.24 mol) and1,1′-bis(diphenylphosphino)ferrocene (0.49 mmol) were added to thereaction mixture at rt under nitrogen atmosphere and the glass tube wassealed. The glass tube was subjected to heating at 100° C. (externaltemperature) for 24 h. The resulting reaction mixture was allowed tocool down to rt and poured into water (50 ml) and extracted with EtOAc(3×75 ml). The combined organic phase was collected, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (neat DCM) yielding tert-butyl(S)-3-((6-cyanoimidazo [1,2-a]pyridin-2-yl) carbamoyl)pyrrolidine-1-carboxylate (2.25 mmol). MS: ES+ 356.53.

Step c.

To a solution of (tert-butyl(S)-3-((6-cyanoimidazo[1,2-a]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(2.25 mmol) in IPA (30 ml) were added hydroxylamine hydrochloride (13.5mmol) and TEA (15.7 mmol) at rt. The reaction mixture was heated at 70°C. for 3 h. The resulting reaction mixture allowed to cool down to rtand poured into water (50 ml) and extracted with EtOAc (3×75 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding tert-butyl(S)-3-((6-(N-hydroxycarbamimidoyl)imidazo[1,2-a]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate (1.28 mmol). This material was used directlyfor the next step without further purification. MS: ES+ 389.48.

Step d.

A solution of tert-butyl(S)-3-((6-(N-hydroxycarbamimidoyl)imidazo[1,2-a]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate (1.28 mmol) in N,N-dimethylacetamidedimethylacetal (20 ml) was heated at 100° C. for 1 h. The resultingreaction mixture allowed to cool down to rt and poured into water (25ml) and extracted with EtOAc (3×25 ml). The combined organic phase wascollected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography(100% DCM) yielding tert-butyl (S)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-2-yl)carbamoyl) pyrrolidine-1-carboxylate (0.70mmol). This material was used directly for the next step without furtherpurification. MS: ES+ 413.54.

Step e.

To a solution of tert-butyl (S)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-2-yl)carbamoyl) pyrrolidine-1-carboxylate (0.70mmol) in DCM (6 ml) was added TFA (1.2 ml) at 0° C. The reaction mixturewas stirred at rt for 1 hr. The resulting reaction mixture wasconcentrated under reduced pressure. The obtained residue was trituratedwith diethyl ether (10 ml) yielding(S)—N-(6-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamideTFA salt (0.69 mmol). The material was used directly for the next stepwithout further purification. MS: ES+ 313.53.

Step f.

To a solution of(S)—N-(6-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamideTFA salt (0.69 mmol) in THF (6 ml) was added K₂CO₃ (2.03 mmol) at 0° C.The reaction mixture was stirred at 0° C. for 30 min. Cyanogen bromide(1.03 mmol) was added to the reaction mixture at 0° C. The reactionmixture was then stirred at rt for 1 h. The resulting reaction mixturewas poured into water (30 ml). The resulting solid precipitates werecollected by filtration under reduced pressure and dried yielding thetitle compound (0.16 mmol). MS: ES+ 338.10; ¹H NMR (400 MHz, DMSO-d₆) δppm 11.06 (br s, 1H), 9.32 (s, 1H), 8.33 (s, 1H), 7.72 (dd, J=9.16, 1.53Hz, 1H), 7.58 (d, J=9.16 Hz, 1H), 3.61-3.65 (m, 1H), 3.41-3.54 (m, 3H),3.28-3.32 (m, 1H), 2.69 (s, 3H), 2.14-2.22 (m, 1H), 2.01-2.10 (m, 1H).

Example 210(±)-trans-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-4-(trifluoromethyl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 109using trans (±) [4-(trifluoromethyl)pyrrolidine]-1,3-dicarboxylic acid1-tert-butyl ester, 2-amino-6-bromoimidazo[1,2-a]pyridine (preparedaccording to the method described in WO2012174312) and3,5-dimethylisoxazole-4-boronic acid. LCMS: Method B, 3.57 min, MS: ES+419.31 Example 211(S)-1-cyano-N-(4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 138using 2-amino-4-bromopyridine and 1-methyl-1H-pyrazole-4-boronic acidpinacol ester. LCMS: Method C, 2.96 min, MS: ES+ 297.02

Example 212(S)-1-cyano-N-(5-(N,N-dimethylsulfamoyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 10, Steps c, f, g)

Step c.

To a solution of Intermediate 14 (0.48 mmol) in DCM (3 ml) were addedTEA (1.44 mmol) and N,N-dimethylaminosulfonyl chloride (0.57 mmol) at 0°C. The reaction mixture was stirred at rt for 2 h. The resultingreaction mixture was poured into water (150 ml) and extracted with EtOAc(3×50 ml). The combined organic phase was collected, washed withsaturated NaHCO₃ (50 ml), 10% citric acid (50 ml), brine (50 ml)solution, dried over Na₂SO₄, filtered and concentrated under reducedpressure yielding tert-butyl(S)-3-((5-(N,N-dimethylsulfamoyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.39 mmol). This material was used directly for the next step withoutfurther purification. MS: ES+ 460.17.

Step f, g.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for steps f and g of Example 202.LCMS: Method B, retention time 3.15 min, MS: ES+ 385.14

Example 213 (S)-1-cyano-N-(5-(pyridazin-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide

(Prepared According to Scheme 14, Steps a,b,d-g)

Step a.

A solution of Intermediate 20 (2.5 mmol) in dry THF (15 ml) was cooledat −78° C. 2.4M n-BuLi in Hexane (2.5 mmol) was added dropwise to thereaction mixture at −78° C. The reaction mixture was stirred at −78° C.for 20 min. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 mmol) was addedto the reaction mixture at −78° C. The reaction mixture was stirred at−78° C. for 30 min. The resulting reaction mixture was allowed to warmto 0° C. and quenched by addition of saturated ammonium chloridesolution (100 ml). The resulting mixture was extracted with EtOAc (2×100ml). The combined organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give tert-butyl(4-methoxybenzyl)-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate(quantitative yield). This material was immediately used for the nextstep without any purification.

Step b.

In a glass sealed tube a suspension of 4-bromopyridazine hydrobromide(1.25 mmol), tert-butyl(4-methoxybenzyl)-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate(2.18 mmol) and Na₂CO₃ (6.25 mmol) in toluene:water (15 ml: 3 ml) wasdegassed with nitrogen for 30 min at it. PdCl₂(dppf) (0.12 mmol) wasadded in to the reaction mixture at rt and the glass tube was sealed.The reaction mixture was heated at 100° C. (external) for 1 h. Theresulting reaction mixture was cooled to rt, poured into saturatedNaHCO₃ solution (300 ml) and extracted with EtOAc (3×150 ml). Thecombined organic phase was washed with brine solution (250 ml), driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography (2.5% MeOH inDCM) yielding tert-butyl(4-methoxybenzyl)(5-(pyridazin-4-yl)thiazol-2-yl)carbamate (1.13 mmol).MS: ES+ 399.35; ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.58-9.60 (m, 1H), 9.15(dd, J=1.2, 5.6 Hz, 1H), 8.38 (s, 1H), 7.82-7.84 (m, 1H), 7.26 (d, J=8.4Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.22 (s, 2H), 3.72 (s, 3H), 1.5 (s,9H).

Step d.

A solution of tert-butyl(4-methoxybenzyl)(5-(pyridazin-4-yl)thiazol-2-yl)carbamate (0.75 mmol)in TFA (15 ml) was heated at 80° C. for 8 h. The resulting reactionmixture was concentrated under reduced pressure and water (75 ml) wasadded to it. The resulting mixture was extracted with EtOAc (3×50 ml).The obtained aqueous layer was basified by using solid NaHCO₃ andextracted with EtOAc (15×50 ml). The combined organic phase was driedover Na₂SO₄, filtered and concentrated under reduced pressure yielding5-(pyridazin-4-yl)thiazol-2-amine (0.67 mmol). This material was usedfor the next step without further purification. MS: ES+ 179.01

Step e.

To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylicacid (1.17 mmol) in THF (7 ml) was added HATU (1.18 mmol) and DIPEA(2.35 mmol) at rt. The reaction mixture was stirred at rt for 2 h.5-(pyridazin-4-yl)thiazol-2-amine (0.78 mmol) was added to the reactionmixture at rt. The reaction mixture was stirred at rt for 2 h. Theresulting reaction mixture was poured into saturated NaHCO₃ solution(100 ml) and extracted with EtOAc (3×50 ml). The combined organic phasewas dried over Na₂SO₄, filtered and concentrated under reduced pressure.The resulting residue was purified by flash chromatography (3.5% MeOH inDCM) yielding tert-butyl(S)-3-((5-(pyridazin-4-yl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.46 mmol). MS: ES+ 376.29; ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.68 (s,1H), 9.58-9.60 (m, 1H), 9.16 (dd, J=1.2, 5.6 Hz, 1H), 8.48 (s, 1H),7.81-7.83 (m, 1H), 3.53-3.54 (m, 1H), 3.28-3.44 (m, 4H), 2.15-2.17 (m,1H), 2.01-2.09 (m, 1H), 1.45 (s, 9H).

Step f, g.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for steps c and d of Example 140.LCMS: Method C, 1.87 min, MS: ES+ 300.88; ¹H NMR (400 MHz, DMSO-d6) δppm 12.78 (s, 1H), 9.58-9.60 (m, 1H), 9.16 (d, J=5.6, 1H), 8.41 (s, 1H),7.82-7.84 (m, 1H), 3.62-3.66 (m, 1H), 3.55-3.59 (m, 1H), 3.41-3.47 (m,2H), 3.37-3.39 (m, 1H), 2.17-2.26 (m, 1H), 2.05-2.13 (m, 1H).

Compounds in Table 7 were synthesised using a procedure similar to thatdescribed for Example 213.

TABLE 7 LCMS Method Aryl halide RT (min) Ex R Name CAS Number MS ES+ 214

(S)-1-cyano-N-(5-(4-cyano-3- fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide 105942-08-3 B  3.85 342.23 215

(S)-N-(5-(1H-indazol-7-yl)thiazol- 2-yl)-1-cyanopyrrolidine-3-carboxamide 53857-58-2 B  3.56 339.33 216

(S)-N-(5-(3-(1H-imidazol-1- yl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide 25372-02-5 C  2.77 364.88 217

(S)-1-cyano-N-(5-(4- (methylsulfonamido)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide 4284-50-8 B  3.27 392.37 218

(S)-N-(5-(3-(1H-pyrazol-1- yl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide 294877-33-1 C  3.40 364.95 219

(S)-1-cyano-N-(5-(4-cyano-3- (trifluoromethoxy)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide 1187983-97-6 C  3.63 407.93 220

(S)-1-cyano-N-(5-(4-cyano-3- methoxyphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide 330793-38-9 C  3.03 353.90 221

(S)-1-cyano-N-(5-(4- sulfamoylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide 701-34-8 C  2.26 377.79 222

(S)-N-(5-(1H-indazol-6-yl)thiazol- 2-yl)-1-cyanopyrrolidine-3-carboxamide 79762-54-2 C/   2.82/ 338.93 223

(S)-N-(5-(1H-indazol-5-yl)thiazol- 2-yl)-1-cyanopyrrolidine-3-carboxamide 53857-57-1 C  2.69 338.93 224

(S)-6-(2-(1-cyanopyrrolidine-3- carboxamido)thiazol-5-yl)-N-methylpicolinamide 337535-94-1 C  2.46 356.96 225

(S)-6-(2-(1-cyanopyrrolidine-3- carboxamido)thiazol-5-yl)-N-ethylpicolinamide 337535-98-5 C  2.65 371.00 226

(S)-1-cyano-N-(5-(1-methyl-1H- indazol-5-yl)thiazol-2-yl)pyrrolidine-3-carboxamide 465529-57-1 C  3.10 352.97

Example 227 (S)-1-cyano-N-(5-(1-(2-methoxyethyl)-1H-indazol-5-yl)thiazol-2-yl)pyrrolidine-3-carboxamide (Prepared According to Scheme 14,Steps c-g)

Step c.

A mixture of Intermediate 20 (0.50 g, 1.25 mmol), Intermediate 18 (0.38g, 1.25 mmol) and Cs₂CO₃ (0.77 g, 2.37 mmol) in 1,4-dioxane:water (9:1)(5 ml) was prepared in a glass vial. The reaction mixture was degassedfor 30 min. Pd(dppf)Cl₂ (0.03 g, 0.03 mmol) was added to the reactionmixture at rt. The glass vial was sealed and subjected to heating at 80°C. (external temperature) for 2 h. The resulting reaction mixture wasdiluted with water (50 ml) and extracted with DCM (3×30 ml). Thecombined organic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (25% EtOAc in hexane) yielding tert-butyl(4-methoxybenzyl)(5-(1-(2-methoxyethyl)-1H-indazol-5-yl)thiazol-2-yl)carbamate(0.37 g, 0.74 mmol). LCMS: Method A, 2.93 min, MS: ES+ 495.6.

Step d-g.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for steps d-g of Example 213. LCMS:Method C, 3.24 min, MS: ES+ 397.02 Example 228(S)-1-cyano-N-(5-(2-oxoindolin-7-yl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 227using CAS number 1150271-45-6 in step c. LCMS: Method C, 2.82 min, MS:ES+ 353.90

Example 229(S)-1-cyano-N-(5-(3-methyl-1H-indazol-5-yl)thiazol-2-yl)pyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 227using CAS number 864771-17-5 in step c. LCMS: Method B, 3.31 min, MS:ES+ 353.57

Example 230 (S)—N-(5-(1H-indazol-4-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 227using Intermediate 19 in step c. LCMS: Method A, 1.82 min, MS: ES+339.54

Example 231(S)-1-cyano-N-(5-(4-fluoro-3-(methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide (Prepared According to Scheme 15)

Step a.

This was carried out using a procedure similar to that described forExample 213 step a. LCMS: Method A, 3.21 min, MS: ES+ 473.40

Step b.

To a solution of methyl5-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)thiazol-5-yl)-2-fluorobenzoate(0.23 g, 0.48 mmol), triazabicyclodecene (0.13 g, 0.97 mmol) in THF (5ml) was added CH₃NH₂ (2M in THF) (1.21 ml, 2.43 mmol) at 0° C. Thereaction mixture was stirred at rt for 4 h. The resulting reactionmixture was poured into water (25 ml) and extracted with EtOAc (3×25ml). The combined organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (35% EtOAc in hexane) yielding tert-butyl(5-(4-fluoro-3-(methylcarbamoyl)phenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate(0.13 g, 0.27 mmol).

LCMS: Method A, 2.87 min, MS: ES+ 472.45

Steps c-f.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 213 steps b-e. LCMS:Method A, 1.81 min, MS: ES+ 374.35 Compounds in Table 8 were synthesisedusing a procedure similar to that described for Example 231.

TABLE 8 LCMS Method Aryl halide RT (min) Ex R Name CAS Number MS ES+ 232

(S)-N-(5-(3- carbamoylphenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide 618-89-3 B  2.88 342.32 233

(S)-1-cyano-N-(5-(3- (methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide 618-89-3 C  2.59 356.07 234

(S)-1-cyano-N-(5-(3- (ethylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide 618-89-3 B  3.18 370.27 235

(S)-1-cyano-N-(5-(3- (dimethylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide 618-89-3 B  3.12 370.27 236

(S)-N-(5-(3-carbamoyl-4- fluorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide 82702-31-6 C  2.49 359.89 237

(S)-N-(5-(3-carbamoyl-4- chlorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide 107947-17-1 A  1.77 376.30 238

(S)-N-(5-(4-chloro-3- (methylcarbamoyl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3- carboxamide 107947-17-1 A  1.82 390.35 239

(S)-N-(5-(4-chloro-3-(prop-2-yn-1- ylcarbamoyl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide 107947-17-1 B  3.59 414.59

Example 240(S)-1-cyano-N-(5-(isopropylsulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrrolidine-3-carboxamide

(Prepared According to Scheme 16, Steps a-j)

Step a.

A solution of 3-nitro-1H-pyrazole-5-carboxylic acid (63.66 mmol) in MeOH(100 ml) and catalytic amount of DMF (0.05 ml) was stirred at 0° C. for10 min. SOCl₂ (165.52 mmol) was added dropwise to the reaction mixtureat 0° C. The reaction mixture was allowed to warm up to rt and thenheated at 70° C. for 4 h. The resulting reaction mixture wasconcentrated under reduced pressure. The obtained residue wasazeotropically distilled using MeOH (100 ml) yielding methyl3-nitro-1H-pyrazole-5-carboxylate (quantitative). MS: ES− 170.12.

Step b.

A solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (65.27 mmol) andK₂CO₃ (326.4 mmol) in acetone (335 ml) was stirred at rt for 20 min.1,2-Dibromoethane (195.81 mmol) was added to the reaction mixture at rtand then stirred at 60° C. for 1 h. The reaction mixture was filteredand the filtrate was concentrated under reduced pressure. The resultingresidue was purified by column chromatography (9-10% EtOAc in hexane)yielding methyl 1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate(41.10 mmol) MS: ES+ 278.05 (M) 280 (M+2); ¹H NMR (400 MHz, DMSO-d₆) δppm 7.63 (s, 1H), 5.01-5.05 (m, 2H), 3.92-3.96 (m, 2H), 3.90 (s, 3H).

Step c.

To a solution of methyl1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (41.11 mmol) in THF(171 ml) was added LiBH₄ (3.0M in THF) (82.21 mmol) at 0° C. Thereaction mixture was stirred at rt for 2 h. EtOAc (125 ml) was added tothe resulting reaction mixture followed by the addition of water (120ml) The organic layer was separated and the aqueous layer was furtherextracted with EtOAc (3×60 ml). The combined organic phase wascollected, washed with brine (60 ml) dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield(1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (39.46 mmol).

This material was directly used for the next step without furtherpurification. MS: ES+ 250 (M) 252 (M+2); ¹H NMR (400 MHz, DMSO-d₆) δ ppm6.99 (s, 1H), 5.68 (t, J=5.2 Hz, 1H), 4.61-4.67 (m, 4H), 3.91 (t, J=6.4Hz, 2H).

Step d.

A solution of (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl) methanol (39.43mmol) in chloroform (394.4 ml) was added PBr₃ (39.43 mmol) dropwise at0° C. The reaction mixture was stirred at rt for 2 h. The resultingreaction mixture was cooled to 0° C. and DCM (1000 ml) added. Themixture was basified with saturated NaHCO₃ solution (400 ml). Theorganic layer was separated and aqueous layer further extracted with DCM(3×400 ml). The combined organic phase was collected, washed with brine(650 ml), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by column chromatography(15% EtOAc in hexane) yielding1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (18.27 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.22 (s, 1H), 4.91 (s, 2H), 4.71 (t, J=6.0Hz, 2H), 3.93 (t, J=6.0 Hz, 2H).

Step e.

To a solution of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole(18.27 mmol), aqueous ammonia (257 ml) in THF (68 ml) was stirred at rtfor 72 h. The reaction mixture was concentrated under reduced pressure.The resulting residue was dissolved in THF (50 ml) and a saturatedsolution of K₂CO₃ (5 ml) added (to neutralise residual HBr). The mixturewas concentrated under reduced pressure and the resulting residue waspurified by column chromatography (4% MeOH in DCM) yielding2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (13.54 mmol). MS: ES+169.04.

Step f.

To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (1.78mmol) in DCM (9 ml) was added TEA (3.56 mmol) and the mixture stirred atrt for 15 min. Methanesulfonyl chloride (1.96 mmol) was added at rt andthe reaction mixture was stirred at rt for 4 h. The reaction mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (40% EtOAc in Hexane) yielding5-(isopropylsulfonyl)-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine(1.51 mmol). MS: ES+ 275.5.

Step g.

To a solution of5-(isopropylsulfonyl)-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine(1.45 mmol) in MeOH (16 ml) was added 10% Pd/C (0.5% w/w) at rt. Thereaction mixture was purged with H₂ gas at rt for 3 h. The resultingreaction mixture was carefully filtered through celite hyflow andconcentrated under reduced pressure to yield5-(isopropylsulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine(1.27 mmol). The material was immediately used for the next step. MS:ES+ 245.2.

Step h.

To a solution of (3S)-BOC-1-pyrrolidine-3-carboxylic acid (1.47 mmol) inTHF (9 ml) was added T3P (50% in EtOAc) (3.65 mmol) at rt. The reactionmixture was stirred for 10 min.5-(Isopropylsulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine(1.22 mmol) and DIPEA (3.68 mmol) were added to the reaction mixture andstirred at rt for 1 h. The resulting reaction mixture was poured intowater (100 ml) and extracted with EtOAc (3×100 ml). The combined organicphase was washed with saturated NaHCO₃ (100 ml) and brine (100 ml)collected, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography (3%MeOH in DCM) yielding tert-butyl(S)-3-((5-(isopropylsulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.9 mmol). MS: ES+ 442.4.

Step i, j.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for steps c and d of Example 140.LCMS: Method C, 2.554 min, MS: ES+ 367.15; ¹H NMR (400 MHz, DMSO-d6) δppm 10.63 (s, 1H), 6.39 (s, 1H), 4.53 (s, 2H), 4.00 (t, J=5.2 Hz, 2H),3.79 (t, J=5.2 Hz, 2H), 3.55-3.59 (m, 1H), 3.37-3.50 (m, 4H), 3.67-3.33(m, 1H), 2.10-2.15 (m, 1H), 1.96-2.01 (m, 1H), 1.23 (d, J=6.8 Hz, 6H).

Example 241(S)-1-cyano-N-(5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrrolidine-3-carboxamide

(Prepared According to Scheme 16, Steps a-e and g-j).

Steps a-e were carried out as described in Example 240

Step f.

A solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (2.97mmol), iodobenzene (3.56 mmol), Xantphos (0.44 mmol), Cs₂CO₃ (8.92 mmol)in 1,4-dioxane (15 ml) was stirred at rt under nitrogen atmosphere in a25 ml glass vial. The reaction mixture was purged with nitrogen for 30min. Pd(OAc)₂ (0.29 mmol) was added to the reaction mixture at rt undernitrogen atmosphere and the glass vial was sealed. The sealed vial wassubjected to heat at 100° C. for 2 h. The resulting reaction mixture wascooled and poured into water (100 ml) and extracted with EtOAc (3×100ml). The combined organic phase was washed with brine solution (100 ml),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography (20% EtOAc inhexane) yielding2-nitro-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine(Quantitative). MS: ES+ 245.43.

Steps g-j.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 240 according to Scheme16 steps g-j.

LCMS: Method B, 3.511 min, MS: ES+ 337.78; ¹H NMR (400 MHz, DMSO-d6) δppm 10.6 (s, 1H), 7.26 (t, J=8.4 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 6.83(t, J=7.6 Hz, 1H), 6.41 (s, 1H), 4.22 (s, 2H), 4.04 (t, J=5.6 Hz, 2H),3.77 (t, J=5.4 Hz, 2H), 3.57 (t, J=7.6 Hz, 1H), 3.72-3.47 (m, 3H),3.15-3.22 (m, 1H), 2.10-2.17 (m, 1H), 1.91-2.02 (m, 1H).

Example 242(S)—N-(5-benzyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1-cyanopyrrolidine-3-carboxamide

(Prepared According to Scheme 16, Steps a-e and g-j).

Steps a-e were carried out as described in Example 240

Step f.

To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (2.08mmol) in MeOH (14 ml) was added benzaldehyde (4.16 mmol) and acetic acid(5 drops) at 0° C. The reaction mixture was stirred at 0° C. for 1 h.NaCNBH₃ (4.16 mmol) was added to the reaction mixture at 0° C. Thereaction mixture was stirred at rt for 1 h. The resulting reactionmixture was poured into water (100 ml) and extracted with EtOAc (3×100ml). The combined organic phase was washed with brine (100 ml), driedover Na₂SO₄, filtered and concentrated under reduced pressure yielding5-benzyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine(quantitative). MS: ES+ 259.48.

Steps g-j.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 240 according to Scheme16 steps g-j.

LCMS: Method C, 3.52 min, MS: ES+ 351.23; ¹H NMR (400 MHz, DMSO-d6) δppm 10.55 (s, 1H), 7.28-7.36 (m, 5H), 6.25 (s, 1H), 3.91 (t, J=5.6 Hz,2H), 3.67 (s, 2H), 3.57 (s, 2H), 3.54 (s, 1H), 3.38-3.47 (m, 3H),3.15-3.19 (m, 1H), 2.87 (t, J=5.2 Hz, 2H), 2.09-2.14 (m, 1H), 1.95-2.00(m, 1H).

Example 243(S)-1-cyano-N-(1-(4-cyano-3-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamideExample 244(S)-1-cyano-N-(1-(2-cyano-5-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 17)

Step a.

To a solution of 2-methoxyethanol (1.08 g, 14.19 mmol) in THF (20 ml)was added NaH (60% in mineral oil) (0.56 g, 14.91 mmol) at 0° C. Thereaction mixture was stirred at rt for 6 h. The reaction mixture wascooled to 0° C. and a solution of 2,4-difluorobenzonitrile (2.0 g, 14.19mmol) in dioxane (20 ml) was added dropwise. The reaction mixture wasstirred at rt for 16 h. The resulting reaction mixture was diluted withwater (100 ml) and extracted with EtOAc (3×100 ml). The combined organicphase was dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography(10% EtOAc in hexane) yielding a regio-isomeric mixture of2-fluoro-4-(2-methoxyethoxy)benzonitrile and4-fluoro-2-(2-methoxyethoxy)benzonitrile (1.5 g, 7.69 mmol). MS: ES+213.20

Step b.

To a solution of 2-fluoro-4-(2-methoxyethoxy)benzonitrile and4-fluoro-2-(2-methoxyethoxy)benzonitrile (0.7 g, 3.59 mmol) in DMF (10ml) was added K₂CO₃ (1.48 g, 10.77 mmol) at rt under nitrogen in amicrowave tube. KI (0.06 g, 0.36 mmol) was added to the reaction mixtureat rt. The reaction mixture was heated at 140° C. for 2 h in amicrowave. The resulting reaction mixture was poured in to water (50 ml)and extracted with EtOAc (2×100 ml). The combined organic phase waswashed with brine solution (50 ml). The organic phase was collecteddried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography (30-40% EtOAc inhexane) yielding a regio-isomeric mixture of2-(2-methoxyethoxy)-4-(4-nitro-1H-imidazol-1-yl)benzonitrile and4-(2-methoxyethoxy)-2-(4-nitro-1H-imidazol-1-yl)benzonitrile (0.55 g,1.91 mmol). MS: ES+ 289.20

Step c.

To a solution of2-(2-methoxyethoxy)-4-(4-nitro-1H-imidazol-1-yl)benzonitrile and4-(2-methoxyethoxy)-2-(4-nitro-1H-imidazol-1-yl)benzonitrile (0.5 g,1.74 mmol) in THF (30 ml) was added 10% dry Pd/C (0.5 g) at rt. Thereaction mixture was purged with H₂ gas at rt for 1 h. The resultingreaction mixture was carefully filtered through celite hyflow. Thefiltrate containing a regio-isomeric mixture of4-(4-amino-1H-imidazol-1-yl)-2-(2-methoxyethoxy) benzonitrile and2-(4-amino-1H-imidazol-1-yl)-4-(2-methoxyethoxy) benzonitrile was usedimmediately for the next step without distillation.

Step d.

To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylicacid (0.42 g, 1.95 mmol) in THF (20 ml) was added HATU (0.89 g, 2.34mmol) and DIPEA (0.68 ml, 3.91 mmol) at rt. The reaction mixture wasstirred at rt for 1 h. The filtrate obtained in step c containingregio-isomeric mixture of4-(4-amino-1H-imidazol-1-yl)-2-(2-methoxyethoxy)benzonitrile and2-(4-amino-1H-imidazol-1-yl)-4-(2-methoxyethoxy)benzonitrile (0.4 g,1.56 mmol) in THF (40 ml) was added dropwise at rt. and stirred for 2 h.The resulting reaction mixture was poured into a saturated solution ofNaHCO₃ (50 ml) and extracted with EtOAc (3×50 ml). The combined organicphase was dried over Na₂SO₄, filtered and concentrated under reducedpressure yielding a regio-isomeric mixture of tert-butyl(S)-3-((1-(4-cyano-3-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)carbamoyl)pyrrolidine-1-carboxylateand tert-butyl(S)-3-((1-(2-cyano-5-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)carbamoyl)pyrrolidine-1-carboxylate (0.81 g, 1.78 mmol). This material was useddirectly for the next step without further purification.

LCMS: Method B, 4.02 min, 4.09 min, MS: ES+ 456.83

Step e, f.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for steps c and d of Example 140,providing a regioisomeric mixture of(S)-1-cyano-N-(1-(4-cyano-3-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamideand(S)-1-cyano-N-(1-(2-cyano-5-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide(0.47 g, 1.24 mmol). LCMS: Method C, 3.44 min, 3.51 min, MS: ES+ 381.05

The regio-isomers were separated by preparative HPLC; mobile phase: (A)100% water (B) 100% Acetonitrile, column: Sunfire C18, 250×19 mm, 5 m,flow rate: 15 ml/min; togive(S)-1-cyano-N-(1-(4-cyano-3-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide.LCMS: Method C, 3.44 min, MS: ES+ 381.05; ¹H NMR (400 MHz, DMSO-d6) δppm 10.79 (s, 1H), 8.36 (d, J=1.6 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.85(d, J=8.4 Hz, 1H), 7.50 (d, J=1.6, 1H), 7.41 (dd, J=2.0 Hz, 8.4 Hz, 1H),4.43 (t, J=4.4 Hz, 2H), 3.75 (t, J=4.4 Hz, 2H), 3.58-3.63 (m, 1H),3.46-3.50 (m, 2H), 3.38-3.44 (m, 1H), 3.33 (s, 3H), 3.24-3.29 (m, 1H),2.13-2.17 (m, 1H), 2.00-2.07 (m, 1H) and(S)-1-cyano-N-(1-(2-cyano-5-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamideLCMS: Method C, 3.35 min, MS: ES+ 381.05; ¹H NMR (400 MHz, DMSO-d6) δppm 10.81 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.69(d, J=1.6 Hz, 1H), 7.28 (d, J=2.4, 1H), 7.18 (dd, J=2.4 Hz, 8.4 Hz, 1H),4.28-4.31 (m, 2H), 3.67-3.70 (m, 2H), 3.58-3.67 (m, 1H), 3.46-3.50 (m,2H), 3.37-3.44 (m, 1H), 3.34 (s, 3H), 3.24-3.17 (m, 1H), 2.13-2.17 (m,1H), 2.00-2.07 (m, 1H).

Example 245(S)-1-cyano-N-(1-(4-cyano-3-(3-morpholinopropoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamideExample 246(S)-1-cyano-N-(1-(2-cyano-5-(3-morpholinopropoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

The title compound was synthesised as a mixture of regioisomers using aprocedure similar to that described for Example 243/244 and separatedafter the final step by preparative HPLC; mobile phase: (A) 0.1% FA inwater (B) Acetonitrile:Methanol (50:50), column: Sunfire C18, 250×19 mm,5 μm, flow rate: 15 ml/min to give(S)-1-cyano-N-(1-(4-cyano-3-(3-morpholinopropoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

LCMS: Method B, 2.79 min, MS: ES+ 450.94; ¹H NMR (400 MHz, DMSO-d₆) δppm 10.82 (s, 1H), 8.36 (d, J=1.6 Hz, 1H), 7.91 (d, J=1.2 Hz, 1H), 7.84(d, J=8.4 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.40 (dd, J=2.0, 8.4 Hz, 1H),4.32 (t, J=6.0 Hz, 2H), 3.58-3.62 (m, 5H), 3.40-3.49 (m, 4H), 3.23-3.35(m, 2H), 2.43 (br s, 4H), 2.12-2.17 (m, 1H), 1.99-2.05 (m, 1H),1.94-1.97 (m, 2H), and(S)-1-cyano-N-(1-(2-cyano-5-(3-morpholinopropoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

LCMS: Method B, 2.58 min, MS: ES+ 450.74; ¹H NMR (400 MHz, DMSO-d₆) δppm 10.79 (s, 1H), 8.01 (d, J=1.2 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.68(d, J=1.2 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.16 (dd, J=2.4, 8.8 Hz, 1H),4.19 (t, J=6.4 Hz, 2H), 3.55-3.58 (m, 5H), 3.41-3.49 (m, 4H), 3.22-3.35(m, 2H), 2.36 (br s, 4H), 2.12-2.17 (m, 1H), 2.00-2.07 (m, 1H),1.87-1.93 (m, 2H).

Example 247(S)-1-cyano-N-(1-(4-cyano-3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamideExample 248(S)-1-cyano-N-(1-(2-cyano-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

The title compound was synthesised as a mixture of regioisomers using aprocedure similar to that described for Example 243/244 and separatedafter the final step by preparative HPLC; Mobile phase: (A) 100% hexane(B) IPA: Methanol (50:50), column: YMC PACKSIL, 250×mm, 5 μm, flow rate:15 ml/min to give(S)-1-cyano-N-(1-(4-cyano-3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide,LCMS: Method B, 3.20 min, MS: ES+ 393.59; ¹H NMR (400 MHz, DMSO-d₆) δppm 10.79 (s, 1H), 8.36 (d, J=1.6 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.86(d, J=8.4 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.42 (dd, J=2.0, 8.4 Hz, 1H),5.48 (s, 1H), 3.86-3.96 (m, 3H), 3.77-3.83 (m, 1H), 3.58-3.62 (m, 1H),3.40-3.49 (m, 3H), 3.24-3.29 (m, 1H), 2.28-2.32 (m, 1H), 2.12-2.17 (m,1H), 2.05-2.07 (m, 2H), and(S)-1-cyano-N-(1-(2-cyano-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide,LCMS. Method B, 3.38 min, MS: ES+ 393.19; ¹H NMR (400 MHz, DMSO-d₆) δppm 10.81 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.67(d, J=2.0 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.17 (dd, J=2.4, 8.4 Hz, 1H),5.28 (t, J=4.0 Hz, 1H), 3.83-3.91 (m, 3H), 3.76-3.79 (m, 1H), 3.58-3.62(m, 1H), 3.24-3.49 (m, 4H), 2.27-2.33 (m, 1H), 2.14-2.18 (m, 1H),1.98-2.05 (m, 1H), 1.88-1.92 (m, 1H).

Example 249(S)-1-cyano-N-(1-(4-cyano-3-(oxetan-3-yloxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamideExample 250(S)-1-cyano-N-(1-(2-cyano-5-(oxetan-3-yloxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide

The title compound was synthesised as a mixture of regioisomers using aprocedure similar to that described for Example 243/244 and separatedafter the final step by preparative HPLC; mobile phase: (A) 100% water(B) 100% Acetonitrile, column: X-bridge C18, 150×19 mm, 5 μm, flow rate:13 ml/min, to give(S)-1-cyano-N-(1-(4-cyano-3-(oxetan-3-yloxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide,LCMS: Method B, 3.31 min, MS: ES+ 379.26; ¹H NMR (400 MHz, DMSO-d₆) δppm 10.79 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.45 (d,J=8.0 Hz, 1H), 7.11 (s, 1H), 5.67 (t, J=4.8 Hz, 1H), 5.00 (t, J=6.8 Hz,2H), 4.60 (t, J=6.4 Hz, 2H), 3.58-3.62 (m, 1H), 3.4-3.49 (m, 3H),3.23-3.27 (m, 1H), 2.12-2.16 (m, 1H), 2.03-2.05 (m, 1H), and(S)-1-cyano-N-(1-(2-cyano-5-(oxetan-3-yloxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide,LCMS: Method B, 3.24 min, MS: ES+ 379.26; ¹H NMR (400 MHz, DMSO-d₆) δppm 10.81 (s, 1H), 7.96-7.99 (m, 2H), 7.67 (d, J=1.6 Hz, 1H), 7.13 (d,J=2.4 Hz, 1H), 7.07 (dd, J=2.4 Hz, 8.4 Hz, 1H), 5.5 (t, J=5.2 Hz, 1H),4.96 (t, J=6.8 Hz, 2H), 4.55-4.58 (m, 2H), 3.58-3.62 (m, 1H), 3.39-3.49(m, 3H), 3.24-3.29 (m, 1H), 2.12-2.16 (m, 1H), 2.00-2.05 (m, 1H).

Example 251(S)-1-cyano-N-(4-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 18)

Step a.

To a solution of 2-amino-4-bromo pyridine (2.50 g, 14.45 mmol) and(S)-1-N-BOC-beta-proline (3.72 g, 17.34 mmol) in pyridine (50 ml) wasstirred at rt for 15 min, phosphorous oxychloride (2.67 ml, 28.90 mmol)was added dropwise to the reaction mixture at 0° C. and then stirred atrt for 1 h. The resulting reaction mixture was poured into water (100ml) and extracted with EtOAc (3×30 ml). The combined organic phase wasdried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography (20% EtOAc inhexane) yielding tert-butyl(S)-3-((4-bromopyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate (5.0 g,13.55 mmol). LCMS: Method A, 2.39 min, MS: ES+ 370.1, 372.1

Step b.

To a solution of tert-butyl(S)-3-((4-bromopyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate (5.0 g,13.50 mmol) in 1,4-dioxane were added his (pinacolato) diboron (5.14 g,20.26 mmol) and potassium acetate (2.64 g, 27.01 mmol) at rt. Thereaction mixture was degassed for 30 min at rt. Pd₂(dba)₃ (0.61 g, 0.67mmol) and X-phos (0.64 g, 1.35 mmol) were added to the reaction mixtureat rt. The reaction mixture was heated at 110° C. for 2 h. The resultingreaction mixture was filtered through celite and washed with MeOH (100ml). The organic phase was concentrated under reduced pressure yieldingtert-butyl(S)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(11.7 g, quantitative). This material was used directly for the nextstep without further purification. LCMS: Method A, 1.71 min, MS: ES+336.5; 280.38

Step c.

A solution of 7-chloropyrazolo[1,5-a]pyrimidine (0.18 g, 1.17 mmol),tert-butyl(S)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(2.43 g, 5.86 mmol) and K₂CO₃ (0.48 g, 3.52 mmol) in DMF (10 ml) wasprepared in a glass vial. The reaction mixture was degassed for 20 min.Pd(dppf)Cl₂ (0.06 g, 0.093 mmol) was added and the reaction mixture washeated at 80° C. for 2 h. The resulting reaction mixture was cooled tort and poured into water (50 ml). The obtained mixture was extractedwith EtOAc (2×50 ml). The combined organic phase was washed with water(100 ml), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography(60% EtOAc in hexane) yielding tert-butyl(S)-3-((4-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate(0.28 g, 0.68 mmol). LCMS: Method A, 2.14 min, MS: ES+ 409.28.

Steps d,e.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 193 steps f,g. LCMS:Method B, 3.23 min, MS: ES+ 334.37; ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.92 (s, 1H), 9.28 (dd, J=7.6 Hz, 0.8 Hz, 1H), 8.91 (s, 1H), 8.52 (d,J=4.8 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.88 (dd, J=5.2 Hz, 1.6 Hz, 1H),7.67 (d, J=7.2 Hz, 1H), 6.92 (dd, J=2.4 Hz, 0.8 Hz, 1H), 3.61-3.65 (m,1H), 3.53-3.57 (m, 1H), 3.37-3.50 (m, 3H), 2.18-2.21 (m, 1H), 2.09-2.12(m, 1H).

Compounds in Table 9 were synthesised using a procedure similar to thatdescribed for Example 251.

TABLE 9 LCMS Method Aryl halide RT (min) Ex R1 Name CAS Number MS ES+252

(S)-1-cyano-N-(4-(imidazo[1,2- a]pyrimidin-5-yl)pyridin-2-yl)pyrrolidine-3-carboxamide 944896-82-6 B  2.46 334.12 253

(S)-1-cyano-N-(4-(imidazo[1,2- a]pyridin-5-yl)pyridin-2-yl)pyrrolidine-3-carboxamide 69214-09-1 C  3.07 333.14 254

(S)-1-cyano-N-(4-(imidazo[1,2- a]pyrazin-6-yl)pyridin-2-yl)pyrrolidine-3-carboxamide 912773-24-1 C  2.85 334.21 255

(S)-1-cyano-N-(4-(imidazo[1,2- a]pyrimidin-6-yl)pyridin-2-yl)pyrrolidine-3-carboxamide 865156-68-9 C  2.69 334.14

Example 256(S)-1-cyano-N-(1,7-naphthyridin-6-yl)pyrrolidine-3-carboxamide (PreparedAccording to Scheme 1)

Step a.

To a solution of 1,7-naphthyridin-6-amine (0.22 g, 0.98 mmol) and(3S)-BOC-1-pyrrolidine-3-carboxylic acid (0.21 g, 0.98 mmol) in DCM (10ml) was added pyridine (0.95 ml, 11.78 mmol) at 0° C. Phosphorousoxychloride (0.75 ml, 7.86 mmol) was added dropwise to the reactionmixture at 0° C. and then stirred at rt for 20 min. The resultingreaction mixture was poured into saturated NaHCO₃ solution (50 ml) andextracted with DCM (3×50 ml). The combined organic phase was collected,washed with brine (25 ml), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography (70-80% EtOAc in n-hexane) yielding tert-butyl (S)-3-((1,7-naphthyridin-6-yl)carbamoyl)pyrrolidine-1-carboxylate (0.12 g, 0.35mmol). LCMS: Method A, 1.90 min, MS: ES+ 343.34.

Step b, c.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for steps c and d of Example 140.LCMS: Method B, 2.72 min, MS: ES+ 268.11

Compounds in Table 10 were synthesised using a procedure similar to thatdescribed for Example 256.

TABLE 10 LCMS Method Amine RT (min) Ex R1 Name CAS Number MS ES+ 257

(S)-N-(6-(3- chlorophenyl)pyrimidin-4-yl)-1-cyanopyrrolidine-3-carboxamide 1192814-53-1 B  4.01 328.17 258

(S)-N-(2′-amino-[4,4′-bipyridin]- 2-yl)-1-cyanopyrrolidine-3-carboxamide Intermediate 24 C  2.82 308.99 259

(S)-1-cyano-N-(2′-(methylamino)- [4,4′-bipyridin]-2-yl)pyrrolidine-3-carboxamide Intermediate 25 C  3.10 323.03 260

(S)-3-(1-cyanopyrrolidine-3- carboxamido)-N- methylisoquinoline-6-carboxamide Intermediate 26 A  1.67 324.39

Example 261(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 5)

Step a.

This was carried out using a procedure similar to that described forExample 138 using 6-bromoisoquinolin-3-amine and3,5-dimethylisoxazole-4-boronic acid pinacol ester.

LCMS: Method A, 1.69 min, MS: ES+ 240.15.

Step b.

To a solution of 6-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-amine (0.30g, 1.25 mmol) and (3S)-BOC-1-pyrrolidine-3-carboxylic acid (0.30 g, 1.38mmol) in DCM (15 ml) was added pyridine (1.10 ml, 13.81 mmol) at 0° C.The reaction mixture was stirred for 20 min at 0° C. Phosphorousoxychloride (1.20 ml, 12.547 mmol) was added dropwise to the reactionmixture at 0° C. and then stirred at rt for 2 hr. The resulting reactionmixture was poured into water (30 ml) and extracted with DCM (3×25 ml).The combined organic phase was collected, washed with 10% citric acidsolution (25 ml) then washed with saturated NaHCO₃ solution (2×30 ml),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography (1% MeOH in DCM)yielding tert-butyl(S)-3-((6-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)carbamoyl)pyrrolidine-1-carboxylate (0.20 g, 0.46 mmol). LCMS: Method A, 2.32 min,MS: ES+ 437.46.

Step c, d.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for steps c and d of Example 138.LCMS: Method B, 4.62 min, MS: ES+ 362.34.

Example 262(S)—N-(4-(1H-indazol-4-yl)pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 261using 1-BOC-4-bromo-1H-indazole and 2-aminopyridine-4-boronic acidpinacol ester. LCMS: Method C, 3.30 min, MS: ES+ 332.94.

Example 263(S)-1-cyano-N-(6-ethynylisoquinolin-3-yl)pyrrolidine-3-carboxamide(Prepared According to Scheme 19)

Step a.

To a solution of 6-bromoisoquinolin-3-amine (0.40 g, 1.79 mmol) and(3S)-BOC-1-pyrrolidine-3-carboxylic acid (0.42 g, 1.97 mmol) in DCM (5ml) was added pyridine (4 ml) at 0° C. POCl₃ (0.34 g, 2.15 mmol) wasadded dropwise to the reaction mixture at 0° C. and stirred for 30 min.The resulting reaction mixture was diluted with water (100 ml) andextracted with EtOAc (3×100 ml). The combined organic layer was washedwith 10% aqueous solution of citric acid (2×50 ml), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography (2% MeOH in DCM) yieldingtert-butyl(S)-3-((6-bromoisoquinolin-3-yl)carbamoyl)pyrrolidine-1-carboxylate(0.39 g, 0.92 mmol). LCMS: Method A, 2.63 min, MS: ES+ 420.28; 422.3

Step b.

The solution of tert-butyl(S)-3-((6-bromoisoquinolin-3-yl)carbamoyl)pyrrolidine-1-carboxylate(0.25 g, 0.59 mmol) and CuI (0.005 g, 0.03 mmol) in diisopropylamine (5ml) was degassed at rt for 15 min. Pd(PPh₃)₂Cl₂ (0.06 g, 0.09 mmol) andtrimethylsilyl acetylene (0.29 g, 2.99 mmol) were added to reactionmixture at rt. The reaction mixture was heated at 120° C. for 30 min.The resulting reaction mixture was concentrated under reduce pressure.The resulting residue was purified by column chromatography (20-25%EtOAc in hexane) yielding tert-butyl (S)-3-((6-((trimethylsilyl)ethynyl)isoquinolin-3-yl)carbamoyl)pyrrolidine-1-carboxylate (0.31g, quantitative). LCMS: Method A, 2.90 min, MS: ES+ 438.72.

Step c.

A solution of tert-butyl(S)-3-((6-((trimethylsilyl)ethynyl)isoquinolin-3-yl)carbamoyl)pyrrolidine-1-carboxylate(0.30 g, 0.68 mmol) in MeOH (5 ml) was added K₂CO₃ (0.24 g, 1.71 mmol)at 0° C. The reaction mixture was stirred at rt for 1 h. The resultingreaction mixture was filtered to remove unreacted K₂CO₃, washed withMeOH (10 ml). The combined filtrate was concentrated under reducedpressure. The resulting residue was purified by flash chromatography(25-30% EtOAc in hexane) yielding tert-butyl(S)-3-((6-ethynylisoquinolin-3-yl)carbamoyl)pyrrolidine-1-carboxylate(0.24 g, 0.65 mmol).

LCMS: Method A, 2.46 min, MS: ES+ 366.28.

Steps d,e.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 193 steps f,g. LCMS:Method C, 4.07 min, MS ES+ 291.10; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.89(s, 1H), 9.17 (s, 1H), 8.48 (s, 1H), 8.05-8.08 (m, 2H), 7.53 (dd, J=8.40Hz, 1.20 Hz, 1H), 4.47 (s, 1H), 3.62-3.66 (m, 1H), 3.48-3.56 (m, 2H),3.34-3.47 (m, 2H), 2.16-2.24 (m, 1H), 2.04-2.13 (m, 1H).

Example 264(2S,3S)-1-cyano-N-(6-ethynylisoquinolin-3-yl)-2-methylpyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 263using Intermediate 1. LCMS: Method C, 4.22 min, MS: ES+ 305.14; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.87 (s, 1H), 9.17 (s, 1H), 8.49 (s, 1H),8.05-8.09 (m, 2H), 7.53 (dd, J=8.40 Hz, 1.20 Hz, 1H), 4.48 (s, 1H),3.97-4.04 (m, 1H), 3.62-3.68 (m, 1H), 3.36-3.45 (m, 2H), 2.17-2.25 (m,1H), 1.99-2.07 (m, 1H), 1.15 (d, J=6.40 Hz, 3H).

Example 265(S)-3-(1-cyanopyrrolidine-3-carboxamido)isoquinoline-6-carboxamide(Prepared According to Scheme 20)

Step a.

To a solution of methyl3-((tert-butoxycarbonyl)amino)isoquinoline-6-carboxylate (preparedaccording to steps a-b of the method described for the synthesis ofIntermediate 26, 0.36 g, 1.19 mmol) in DCM (15 ml) was added TFA (3.6ml) at 0° C. The reaction mixture was stirred at rt for 3 h. Theresulting reaction mixture was concentrated under reduced pressure. Theresulting residue was triturated with Et₂O (10 ml) and dried to yieldmethyl 3-aminoisoquinoline-6-carboxylate TFA salt (0.37 g, 1.15 mmol).LCMS: Method A, 1.66 min, MS: ES+ 203.18. This material was useddirectly for the next step without further purification.

Step b.

To a solution of methyl 3-aminoisoquinoline-6-carboxylate TFA salt (0.35g, 1.11 mmol) and (3S)-BOC-1-pyrrolidine-3-carboxylic in DCM (20 ml) wasadded pyridine (1.34 ml, 16.61 mmol) at 0° C. Phosphorous oxychloride(1.06 ml, 11.07 mmol) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at rt for 20 min. The resultingreaction mixture was poured into saturated NaHCO₃ solution (50 ml) andextracted with DCM (2×50 ml). The combined organic phase was collected,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography (2% MeOH in DCM)yielding methyl(S)-3-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)isoquinoline-6-carboxylate(0.27 g, 0.68 mmol).

LCMS: Method A, 2.26 min, MS: ES+ 400.42.

Step c.

A solution of LiOH (0.26 g, 6.26 mmol) in 5 ml water was added to asolution of methyl(S)-3-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)isoquinoline-6-carboxylate(0.25 g, 0.63 mmol) in MeOH (10 ml) at rt. The reaction mixture washeated at 60° C. for 3 h. The resulting reaction mixture was allowed tocool to rt. The resulting reaction mixture was concentrated underreduced pressure to remove the organic solvent. The resulting aqueouslayer was poured in to the citric acid solution (50 ml) under continuousstirring. The resulting mixture was extracted with EtOAc (3×50 ml). Thecombined organic phase was collected dried over Na₂SO₄, filtered andconcentrated under reduced pressure yielding(S)-3-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)isoquinoline-6-carboxylicacid (0.21 g, 0.54 mmol). LCMS: Method A, 2.04 min, MS: ES+ 386.5.

Step d.

A mixture of(S)-3-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)isoquinoline-6-carboxylicacid (0.2 g, 0.52 mmol), HATU (0.30 g, 0.78 mmol) and DIPEA (0.18 ml,1.04 mmol) in THF (5 ml) was prepared at 0° C. The reaction mixture wasstirred at rt for 0.5 h. Ammonium bicarbonate (0.08 g, 1.04 mmol) wasadded in to the reaction mixture at rt. The reaction mixture was stirredat rt for 42 h. The resulting reaction mixture was poured into saturatedNaHCO₃ solution (40 ml) and extracted with EtOAc (2×50 ml). The combinedorganic phase was collected, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (3% MeOH in DCM) yielding tert-butyl(S)-3-((6-carbamoylisoquinolin-3-yl)carbamoyl)pyrrolidine-1-carboxylate(0.065 g, 0.17 mmol). LCMS: Method A, 1.92 min, MS: ES+ 385.55.

Steps e,f.

The title compound was synthesised from the intermediate above using aprocedure similar to that described for Example 193 steps f,g. LCMS:Method B, 2.73 min, MS: ES+ 310.5 Example 266(2S,3S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-cyano-2-methylpyrrolidine-3-carboxamide

Synthesised using a procedure similar to that described for Example 193,steps f,g, using Intermediate 27. LCMS: Method C, 3.29 min, MS: ES+347.58; ¹H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br s, 1H), 10.75 (s, 1H),9.05 (s, 1H), 8.43-8.47 (m, 2H), 8.13-8.16 (m, 2H), 8.02 (d, J=8.40 Hz,1H), 7.83 (d, J=8.40 Hz, 1H), 3.97-4.04 (m, 1H), 3.63-3.68 (m, 1H),3.34-3.45 (m, 2H), 2.18-2.27 (m, 1H), 1.99-2.07 (m, 1H), 1.16 (d, J=6.40Hz, 3H).

Compounds in Table 11 were synthesised using a procedure similar to thatdescribed for Example 1.

TABLE 11 LCMS Method Amine RT (min) Ex R1 Name CAS Number MS ES+ 267

(S)-1-cyano-N-(pyrazolo[1,5- a]pyridin-2-yl)pyrrolidine-3- carboxamide51119-05-2 B  3.00 256.63 268

(S)-1-cyano-N-(4- phenylpyridin-2-yl)pyrrolidine- 3-carboxamide60781-83-1 B  3.52 293.33 269

(S)-1-cyano-N-(5-(pyridin-3- yl)thiazol-2-yl)pyrrolidine-3- carboxamide372096-52-1 B  2.56 300.18 270

(S)-1-cyano-N-(6- (trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3- carboxamide 1005785-87-4 B  3.42 324.22271

(S)-1-cyano-N-(1-methyl-5-(m- tolyl)-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide 1505611-26-6 C  4.04 310.14 272

(S)-1-cyano-N-(quinolin-3- yl)pyrrolidine-3-carboxamide 580-17-6 C  3.30267.10 273

(S)-N-(4-(tert-butyl)pyridin-2- yl)-1-cyanopyrrolidine-3- carboxamide33252-26-5 B  3.25 273.25 274

(S)-1-cyano-N-(6-(pyridin-4- yl)pyrimidin-4-yl)pyrrolidine-3-carboxamide 1192814-38-2 B  2.35 295.23 275

(S)-1-cyano-N-(5- phenylpyridazin-3- yl)pyrrolidine-3-carboxamide105537-97-1 C  3.43 293.96 276

(S)-1-cyano-N-(6-(oxazol-5- yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide Intermediate 28 C  2.90 323.03 277

(S)-1-cyano-N-(6- (isopropylsulfonyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5- d]azepin-2-yl)pyrrolidine-3- carboxamideIntermediate 29 B  3.27 398.32 278

(S)-1-cyano-N-(1-(4-(1-(2- methoxyethyl)-1H-pyrazol-4-yl)phenyl)-1H-imidazol-4- yl)pyrrolidine-3-carboxamide Intermediate 30 B 3.23 406.65

Compounds in Table 12 were synthesised using a procedure similar to thatdescribed for Example 1 using 2-amino-5-phenylthiazole.

TABLE 12 LCMS Method Acid CAS RT (min) Ex —R Name Number MS ES+ 279

3-cyano-N-(5-phenylthiazol-2- yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 1363381-55-8 B  3.93 311.10 280

2-cyano-N-(5-phenylthiazol-2- yl)-2-azabicyclo[3.1.0]hexane-4-carboxamide 1258652-53-7 C 3.61 and 3.81 311.10 281

(3S,4S)-1-cyano-N-(5- phenylthiazol-2-yl)-4-(trifluoromethyl)pyrrolidine-3- carboxamide 1212064-03-3 B  4.28 367.30282

trans-1-cyano-N-(5- phenylthiazol-2-yl)-4-(pyridin-3-yl)pyrrolidine-3-carboxamide Intermediate 31 C  3.17 375.95 283

trans-1-cyano-N-(5- phenylthiazol-2-yl)-4-(pyrimidin-5-yl)pyrrolidine-3-carboxamide Intermediate 32 C  2.84 376.93 284

1-cyano-3-methoxy-N-(5- phenylthiazol-2-yl)pyrrolidine-3- carboxamideIntermediate 33 C  3.14 328.95

Compounds in Table 13 were synthesised using a procedure similar to thatdescribed for Example 109.

TABLE 13 Aryl halide/Aryl LCMS Method Boronate RT (min) Ex R1 Name CASNumber MS ES+ 285

(S)-1-cyano-N-(6-(3,5- dimethylisoxazol-4- yl)thiazolo[4,5-b]pyridin-2-yl)pyrrolidine-3- carboxamide 857970-06-0/ 16114-47-9 C  2.45 368.98 286

(9-1-cyano-N-(5-(3,5- dimethylisoxazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)pyrrolidine-3- carboxamide 934266-82-7/ 16114-47-9 C  2.03 369.49 287

(S)-1-cyano-N-(6-(2,6- dimethylphenyl)benzo[d]thia-zol-2-yl)pyrrolidine-3- carboxamide 15864-32-1/ 100379-00-8 C  4.31377.13 288

(S)-1-cyano-N-(6-(1,3- dimethyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)pyrrolidine-3- carboxamide 15864-32-1/ 1046832-21-6 C  2.86 367.0 289

(S)-1-cyano-N-(6-(5- (trifluoromethyl)-1H- pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3- carboxamide 891785-28-7/ 1218790-40-9 B  3.70 401.51290

(S)-1-cyano-N-(4-(3-(5- methylisoxazol-4- yl)phenyl)pyridin-2-yl)pyrrolidine-3- carboxamide 1369139-84-3/ 1346808-41-0 C  4.08 373.99291

(S)-N-(4-(1H-pyrazol-4- yl)pyridin-2-yl)-1- cyanopyrrolidine-3-carboxamide 84249-14-9/ 269410-08-4 B  2.25 283.28 292

(S)-N-(6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)-1- cyanopyrrolidine-3-carboxamide 15864-32-1/ 269410-08-4 B  3.09 339.28 293

(S)-N-(6-(1H-pyrazol-4- yl)isoquinolin-3-yl)-1- cyanopyrrolidine-3-carboxamide 891785-28-7/ 269410-08-4 B  2.94 333.30 294

(S)-N-(1-(4-(1H-pyrazol-4- yl)phenyl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3- carboxamide 1368048-03-6/ 269410-08-4 C  2.91348.04 295

(S)-1-cyano-N-(4-(5-methyl- 1H-pyrazol-4-yl)pyridin-2- yl)pyrrolidine-3-carboxamide 84249-14-9/ 936250-20-3 C  2.77 297.02 296

S)-1-cyano-N-(6-(3,5- dimethylisoxazol-4- yl)thiazolo[4,5-d]pyridin-2-yl)pyrrolidine-3- carboxamide 1244058-73-8/ 16114-47-9 C  2.45 369.02297

(S)-1-cyano-N-(2′-(5- methylisoxazol-4-yl)-[4,4′-bipyridin]-2-yl)pyrrolidine- 3-carboxamide Intermediate 34/ 1346808-41-0B  3.67 375.49

Compounds in Table 14 were synthesised using a procedure similar to thatdescribed for Example 150.

TABLE 14 LCMS Method Amine CAS RT (min) Ex R1 Name Number MS ES+ 298

(S)-1-cyano-N-(1-(1,3-dimethyl-1H- indazol-5-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide 5757-85-7 C  3.27 350.04 299

(S)-1-cyano-N-(1-(3-methyl-1H- indazol-6-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide 79173-62-9 B  2.87 336.22 300

(S)-N-(1-(1H-indazol-5-yl)-1H- imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide 19335-11-6 C  2.78 321.97 301

(S)-N-(1-(1H-indazol-6-yl)-1H- imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide 6967-12-0 C  2.97 321.97 302

(S)-1-cyano-N-(1-(4-fluoro-3- methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide 64465-53-8 C  3.67 329.95 303

(S)-N-(1-(1H-indazol-4-yl)-1H- imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide 41748-71-4 C  2.93 321.97 304

(S)-1-cyano-N-(1-(4-cyano-3- cyclopropylphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide Intermediate 35 C  3.86 347.18

Compounds in Table 15 were synthesised using a procedure similar to thatdescribed for Example 174.

TABLE 15 LCMS Method Aryl halide RT (min) Ex R1 Name CAS Number MS ES+305

(S)-1-cyano-N-(1-(quinolin-4-yl)- 1H-imidazol-4-yl)pyrrolidine-3-carboxamide 3964-04-3 C  3.17 332.94 306

(S)-1-cyano-N-(1-(2-cyano-5- cyclopropylphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide 1394068-31-5 C  3.90 346.98 307

(S)-1-cyano-N-(1-(4-cyano-3- methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide 191014-55-8 B  3.25 337.30 308

(S)-1-cyano-N-(1-(4-cyano-3- methylphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide 147754-12-9 C  3.52 320.97 309

(S)-1-cyano-N-(1-(4-cyano-3- (trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3- carboxamide 194853-86-6 C  3.92 374.99 310

(S)-1-cyano-N-(1-(4-cyano-3- (trifluoromethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3- carboxamide 1323966-32-0 C  3.99 390.96

Biological Activity of Compounds of the Invention Abbreviations

TAMRA carboxytetramethylrhodaminePCR polymerase chain reactionPBS phosphate buffered salineEDTA ethylenediaminetetraacetic acidTris 2-amino-2-(hydroxymethyl)-1,3-propanediolNP-40 Nonidet P-40, octylphenoxypolyethoxyethanolBSA bovine serum albumin

In Vitro UCHL1 Inhibition Assay Expression and Purification of UCHL1

The UCHL1 construct was PCR amplified and cloned into a pFLAG-CMV-6avector (Sigma-Aldrich) with an N-terminal FLAG tag. HEK293T cells weretransfected with FLAG-UCHL1 using TranslT-LT1 transfection reagent(Mirus) according to the manufacturer's instructions. Cells wereharvested 40 hours after transfection. Cells were washed once with PBSand scraped in lysis buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 3 mM EDTA,0.5% NP40, 10% glycerol, 5 mM beta-mercaptoethanol, protease inhibitors(complete mini, Roche) and phosphatase inhibitors (PhosSTOP mini,Roche). Lysates were incubated for 30 min on ice and centrifuged at 1200rpm for 10 min at 4° C. Soluble supernatant was added to FLAG affinityresin (EZview Rad ANTI-FLAG M2 affinity gel, Sigma-Aldrich) equilibratedin low salt buffer (20 mM Tris, pH 7.5, 150 mM NaCl, 0.5 mM EDTA, 5 mMbeta-mercaptoethanol) and incubated at 4° C. for 3 hours rotating. Theresin was spun at 2000 rpm for 2 min and the supernatant was removed.The resin was washed two times with low salt buffer and one time withhigh salt buffer (20 mM Tris, pH 7.5, 500 mM NaCl, 0.5 mM EDTA, 5 mMbeta-mercaptoethanol, protease inhibitors (complete mini, Roche) andphosphatase inhibitors (PhosSTOP mini, Roche). To elute the bound UCHL1,elution buffer (10 mM Tris, pH 7.5, 150 mM NaCl, 0.5 mM EDTA, 10%glycerol, 0.5% NP40, 5 mM beta-mercaptoethanol, 0.15 mg/ml 3× FLAGpeptide (Sigma-Aldrich)) was added to the resin and incubated at 4° C.for 2.5 hours rotating. The resin was centrifuged at 4000 rpm for 30seconds, and the supernatant containing purified FLAG-UCHL1 was removedand stored at −80° C.

UCHL1 Biochemical Kinetic Assay

Reactions were performed in duplicate in black 384 well plates (smallvolume, Greiner 784076) in a final reaction volume of 21 μl. UCHL1 wasdiluted in reaction buffer (20 mM Tris, pH 7.5, 100 mM NaCl, 0.05% Tween20, 0.5 mg/ml BSA, 5 mM—beta mercaptoethanol) to the equivalent of 0,0.01, 0.05, 0.1, 0.5, and 1 μl/well. Buffer was optimised for optimaltemperature, pH, reducing agent, salts, time of incubation, anddetergent. Reactions were initiated by the addition of 50 nM of TAMRAlabelled peptide linked to ubiquitin via an iso-peptide bond asfluorescence polarisation substrate. Reactions were incubated at roomtemperature and read every 2 min for 120 min. Readings were performed ona Pherastar Plus (BMG Labtech). λ Excitation 540 nm; λ Emission 590 nm.

UCHL1 Biochemical IC50 Assay

Dilution plates were prepared at 21 times the final concentration (2100μM for a final concentration of 100 μM) in 50% DMSO in a 96-wellpolypropylene V-bottom plate (Greiner #651201). A typical 8-pointdilution series to be 100, 30, 10, 3, 1, 0.3, 0.1, 0.03 μM final.Reactions were performed in duplicate in black 384 well plates (smallvolume, Greiner 784076) in a final reaction volume of 21 μl. Either 1 μlof 50% DMSO or diluted compound was added to the plate. UCHL1 wasdiluted in reaction buffer (20 mM Tris, pH 7.5, 100 mM NaCl, 0.05% Tween20, 0.5 mg/ml BSA, 5 mM—beta mercaptoethanol) to the equivalent of 0.05μl/well and 10 μl of diluted UCHL1 was added to the compound. Enzyme andcompound were incubated for 30 min at room temp. Reactions wereinitiated by the addition of 50 nM of TAMRA labelled peptide linked toubiquitin via an iso-peptide bond as fluorescence polarisationsubstrate. Reactions were read immediately after addition of substrateand following a 2 hr incubation at room temperature. Readings wereperformed on a Pherastar Plus (BMG Labtech). λ Excitation 540 nm; λEmission 590 nm.

Activity of Exemplary Compounds in UCHL1 Biochemical IC50 Assay RangesA<1 μM; 1<B<10 μM; 10<C<30 μM

Example Activity Number range 1 A 2 A 3 B 4 A 5 B 6 B 7 B 8 B 9 C 10 C11 B 12 B 13 B 14 B 15 B 16 C 17 B 18 B 19 B 20 B 21 B 22 B 23 C 24 C 25C 26 C 27 C 28 B 29 B 30 C 31 B 32 B 33 B 34 B 35 B 36 C 37 C 38 B 39 C40 B 41 A 42 A 43 A 44 B 45 C 46 C 47 A 48 B 49 B 50 B 51 A 52 B 53 B 54B 55 B 56 C 57 A 58 B 59 A 60 A 61 B 62 A 63 B 64 A 65 A 66 A 67 A 68 A69 A 70 B 71 C 72 A 73 A 74 A 75 A 76 A 77 B 78 B 79 C 80 C 81 B 82 A 83B 84 B 85 B 86 A 87 B 88 B 89 C 90 C 91 A 92 A 93 A 94 A 95 A 96 A 97 A98 B 99 A 100 A 101 A 102 B 103 B 104 A 105 B 106 C 107 B 108 B 109 B110 B 111 A 112 A 113 A 114 A 115 B 116 A 117 A 118 A 119 B 120 A 121 B122 B 123 A 124 A 125 A 126 A 127 A 128 A 129 A 130 A 131 A 132 A 133 A134 B 135 B 136 B 137 A 138 A 139 A 140 A 141 B 142 B 143 B 144 B 145 B146 A 147 A 148 B 149 A 150 A 151 A 152 A 153 A 154 A 155 A 156 A 157 B158 A 159 A 160 A 161 A 162 A 163 A 164 A 165 B 166 A 167 A 168 A 169 A170 A 171 B 172 B 173 A 174 A 175 B 176 B 177 A 178 A 179 A 180 A 181 A182 A 183 A 184 A 185 A 186 A 187 A 188 B 189 A 190 A 191 A 192 A 193 A194 A 195 A 196 A 197 B 198 A 199 B 200 B 201 B 202 A 203 A 204 A 205 A206 A 207 B 208 A 209 A 210 A 211 B 212 A 213 A 214 A 215 A 216 A 217 A218 A 219 A 220 A 221 A 222 A 223 A 224 A 225 A 226 A 227 A 228 A 229 A230 A 231 A 232 A 233 A 234 A 235 A 236 A 237 A 238 A 239 A 240 A 241 A242 A 243 A 244 A 245 A 246 A 247 A 248 B 249 A 250 A 251 A 252 B 253 A254 A 255 A 256 B 257 B 258 B 259 B 260 B 261 A 262 A 263 B 264 B 265 B266 A 267 B 268 B 269 A 269 B 270 A 271 A 272 B 273 B 274 B 275 B 276 A277 A 278 A 279 B 280 B 281 A 282 B 283 B 284 A 285 B 286 A 287 A 288 A289 A 290 A 291 B 292 B 294 A 295 B 296 C 297 A 298 A 299 A 300 A 301 A302 A 303 A 304 A 305 A 306 A 307 A 308 A 309 A 310 A

1-17. (canceled)
 18. A compound of formula (I):

a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein: R₁ represents a 5 to 10-memberedheteroaryl ring; R₂, R₃, R₄, R₅, R₆ and R₈ each independently representa hydrogen atom, cyano, C₁-C₃ alkyl, C₁-C₃ alkoxy group, or R₂ is linkedto R₈ to form a C₃-C₄ cycloalkyl ring, or R₆ is linked to R₇ to form aC₃-C₄ cycloalkyl ring; wherein said alkyl, alkoxy and cycloalkyl groupsmay be optionally substituted with one or more substituents, which maybe the same or different, selected from halo, deutero, C₁₋₃ alkyl, C₁₋₃alkoxy, and cyano; R₇ represents a hydrogen atom, a fluorine atom,cyano, C₁-C₃ alkyl, CF₃, C₁-C₃ alkoxy group or an aryl or heteroarylring or is linked to R₈ to form a spirocyclic group or is linked to R₆to form a C₃-C₄ cycloalkyl ring; wherein R₁ may be optionallysubstituted with one or more of Q₁-(R₉)_(n); n is 0 or 1; Q₁ representsa hydrogen atom, a halogen atom, cyano, a covalent bond, —NR₁₀—,—CONR₁₀—, —NR₁₀CO—, an oxygen atom, oxo, nitro, —S(O)_(m)—, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, —CO—, —SO₂R₁₁, —NR₁₁R₁₂,—NR₁₁COR₁₂, —NR₁₀CONR₁₁R₁₂, —CONR₁₁R₁₂, —CO₂R₁₁, —NR₁₁CO₂R₁₂,—SO₂NR₁₁R₁₂, —C(O)R₁₁, —NR₁₁SO₂R₁₂, NR₁₁SO₂NR₁₃R₁₄, and SO₂NR₁₁, C₁-C₆alkylene, —C₂-C₆ alkenylene, —C₁-C₆ alkyl, or C₁-C₂ haloalkyl group; mis 0, 1 or 2; R₉ represents a 3 to 10-membered heterocyclyl, heteroaryl,aryl or cycloalkyl ring; and R₁₀, R₁₁ and R₁₂ each independentlyrepresent a hydrogen atom, a C₁-C₆ alkyl, or a C₁-C₆ alkylene group;wherein R₉ may be optionally substituted with one or more substituentsselected from halogen, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, oxo,cyano, nitro, heterocyclyl, cycloalkyl, heteroaryl, aryl,-Q₂-NR₁₃CONR₁₄R₁₅, -Q₂-NR₁₃R₁₄, -Q₂-NR₁₃COR₄, -Q₂-COR₁₃, -Q₂-SO₂R₁₃,-Q₂-CONR₁₃, Q₂-CONR₁₃R₁₄, -Q₂-CO₂R₁₃, -Q₂-SO₂NR₁₃R₁₄, -Q₂-NR₁₃SO₂R₁₄,and -Q₂-NR₁₃SO₂NR₁₄R₁₅; wherein said alkyl, alkoxy and heteroaryl groupsmay be optionally substituted with halo, deutero, C₁₋₃ alkyl, hydroxy,C₁₋₃ alkoxy, cyano, amino, nitro, oxo, aryl, heteroaryl, heterocyclyl,C₃-C₆ cycloalkyl, C₁₋₃ alkylamino, C₂₋₆ alkenylamino, di-C₁₋₃alkylamino, C₁₋₃ acylamino, di-C₁₋₃ acylamino, carboxy, C₁₋₃alkoxycarbonyl, carbamoyl, mono-C₁₋₃ carbamoyl, di-C₁₋₃ carbamoyl or anyof the above in which a hydrocarbyl moiety is itself substituted byhalo; or R₉ may be substituted with a 3 to 10-membered heterocyclyl,heteroaryl, aryl or cycloalkyl ring either directly attached or vialinking group selected from oxygen, a carbonyl, an optionallysubstituted C₁-C₆ alkylene or an optionally substituted C₁-C₆alkyleneoxy chain; Q₂ represents a covalent bond or a C₁-C₆ alkylene orC₂-C₆ alkenylene group; and R₁₃, R₁₄ and R₁₅ each independentlyrepresent hydrogen, C₁-C₆ alkyl, heterocyclyl, heteroaryl, aryl, orcycloalkyl; wherein said alkyl group may be optionally substituted withhalo, deutero, C₁₋₃ alkyl, hydroxy, C₁₋₃ alkoxy, cyano, amino, nitro,oxo, aryl, heteroaryl, heterocyclyl, C₃-C₆ cycloalkyl, C₁₋₃ alkylamino,C₂₋₆ alkenylamino, di-C₁₋₃ alkylamino, C₁₋₃ acylamino, di-C₁₋₃acylamino, carboxy, C₁₋₃ alkoxycarbonyl, carbamoyl, mono-C₁₋₃ carbamoyl,di-C₁₋₃ carbamoyl or any of the above in which a hydrocarbyl moiety isitself substituted by halo.
 19. The compound according to claim 18,wherein R₁ is a 5 to 10-membered monocyclic or bicyclic heteroaryl ringcomprising 1 to 3 heteroatoms independently selected from nitrogen,oxygen and sulphur, and which may be optionally substituted with 1 to 4Q₁-(R₉)_(n).
 20. The compound according to claim 18, wherein theheteroaryl ring of R₁ is a 5 or 6-membered heteroaryl ring or a9-membered bicyclic heteroaryl ring.
 21. The compound according to claim18, wherein the ring of R₁ is selected from thiazolyl, pyridinyl,isoxazolyl, thiadiazolyl, indazolyl, imidazolyl, benzothiazolyl,benzoimidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, napthyridinyl,pyrazinyl, isoquinolinyl, quinolinyl, tetrahydrothiazolopyridinyl,imidazopyridinyl, triazolyl, pyrazolopyridinyl,tetrahydropyrazolopyrazinyl, tetrahydrothiazoloazepinyl andthiazolopyridinyl.
 22. The compound according to claim 18, wherein foreach Q₁-(R₉)_(n) where n is 0, each Q₁ substituent may be independentlyselected from a halogen atom, C₁-C₄ alkyl, C₁-C₂ haloalkyl, C₁-C₂alkoxy, —COR₁₁, —SO₂R₁₁, cyano, CONR₁₁R₁₂ and C₁-C₂ haloalkoxy; andwherein for each Q₁-(R₉)_(n) where n is 1, each Q₁ substituent may beindependently selected from a covalent bond, —CO—, a C₁-C₆ alkylene,C₂-C₆ alkenylene group, and —NR₁₀.
 23. The compound according to claim18, wherein R₂ represents hydrogen, cyano, methyl, or methoxy, whereinthe methyl group is optionally substituted by fluoro, chloro or methoxy.24. The compound according to claim 18, wherein R₇ represents hydrogen,methyl, CF₃, phenyl, pyridyl, or pyrimidyl.
 25. The compound accordingto claim 18, wherein R₂, R₃, R₄, R₅, R₆, R₇ and R₈ each independentlyrepresent hydrogen.
 26. The compound according to claim 18, wherein R₃represents methyl.
 27. The compound according to claim 18, wherein thering of R₉ is a 5 or 6-membered monocyclic, or a 9 or 10-memberedbicyclic, heterocyclyl, aryl, heteroaryl or cycloalkyl ring.
 28. Thecompound according to claim 27, wherein the ring of R₉ is selected frommorpholinyl, piperidinyl, pyrrolidinyl, diazepanyl, piperazinyl,pyridazinyl, pyrazinyl, pyrazolyl, cyclopropyl, cyclohexyl, cyclopentyl,pyridinyl, imidazolyl, indolinyl, isoindolinyl, pyrimidinyl, isoxazolyl,dihydroindenyl, dihydroisoquinolinyl, tetrahydropyranyl, phenyl,oxadiazolyl, triazolyl, isoquinolinyl, indazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, imidazolpyridinyl, imidazopyrimidinyl,imidazopyrazinyl, oxazolyl and quinolinyl.
 29. The compound according toclaim 18, wherein: R₉ may be optionally substituted with one or moresubstituents selected from halogen, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl, oxo, cyano, nitro, heterocyclyl, cycloalkyl, heteroaryl,aryl, -Q₂-NR₁₃CONR₁₄R₁₅, -Q₂-NR₁₃R₁₄, -Q₂-NR₁₃COR₁₄, -Q₂-COR₁₃,-Q₂-SO₂R₁₃, -Q₂-CONR₁₃, Q₂-CONR₁₃R₁₄, -Q₂-CO₂R₁₃, -Q₂-SO₂NR₁₃R₁₄,-Q₂-NR₁₃SO₂R₁₄ and -Q₂-NR₁₃SO₂NR₁₄R₁₅; wherein said alkyl, alkoxy andheteroaryl groups may be optionally substituted with halo, deutero, C₁₋₃alkyl, hydroxy, C₁₋₃ alkoxy, cyano, amino, nitro, or oxo; or R₉ may besubstituted with a 3 to 10 membered heterocyclyl, heteroaryl, aryl orcycloalkyl ring, either directly attached or via linking group selectedfrom oxygen, a carbonyl, an optionally substituted C₁-C₆ alkylene or anoptionally substituted C₁-C₆ alkyleneoxy chain; Q₂ represents a covalentbond or a C₁-C₆ alkylene or C₂-C₆ alkenylene group; and R₁₃, R₁₄ and R₁₅each independently represent hydrogen, C₁-C₆ alkyl, heterocyclyl,heteroaryl, aryl, or cycloalkyl; wherein said alkyl group may beoptionally substituted with halo, deutero, C₁₋₃ alkyl, hydroxy, C₁₋₃alkoxy, cyano, amino, nitro, or oxo.
 30. The compound according to claim29, wherein R₉ may be optionally substituted with 1 to 3 substituentsselected from halogen, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₁-C₆ alkyl, C₂-C₆ alkynyl, oxo, cyano, cycloalkyl, heteroaryl, NR₁₃R₁₄,NR₁₃COR₁₄, CH₂NR₁₃COR₁₄, COR₁₃, CONR₁₃R₁₄, SO₂NR₁₃R₁₄, and NR₁₃SO₂R₁₄;or R₉ may be substituted with a 3 to 10-membered heterocyclyl,heteroaryl, aryl or cycloalkyl ring, either directly attached or vialinking group selected from oxygen, a carbonyl, an optionallysubstituted C₁-C₆ alkylene or an optionally substituted C₁-C₆alkyleneoxy chain; and R₁₃, R₁₄ and R₁₅ each independently representhydrogen, C₁-C₆ alkyl, or phenyl.
 31. The compound according to claim18, having the formula (IV),

a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein Y represents the remaining atoms of a 5 or6 membered heteroaryl ring which may optionally substituted or fusedwith further ring which may be further optionally substituted, whereinsaid optional substituents are as defined in claim
 18. 32. A method oftreating of cancer, neurodegenerative disorders, COPD, inflammation,viral or bacterial infections or metabolic disorders, comprising thestep of administering a compound according to claim 18 or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer, to a patient in need thereof.
 33. A pharmaceutical compositioncomprising a compound claim 18, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, togetherwith one or more pharmaceutically acceptable excipients.
 34. Apharmaceutical composition, comprising a compound selected from thegroup consisting of:(S)-1-cyano-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(3-fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(2-fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;N-(5-(4-chlorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;N-(5-(3-chlorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;N-(5-(2-chlorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(5-methylthiazol-2-yl)pyrrolidine-3-carboxamide;N-(5-(tert-butyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(2-phenylthiazol-5-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-phenyl-1,3,4-thiadiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(3-phenylisoxazol-5-yl)pyrrolidine-3-carboxamide;1-cyano-N-(3-(4-methoxyphenyl)isoxazol-5-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-phenylisoxazol-3-yl)pyrrolidine-3-carboxamide;N-(5-(tert-butyl)isoxazol-3-yl)-1-cyanopyrrolidine-3-carboxamide;N-(3-(tert-butyl)-1H-pyrazol-5-yl)-1-cyanopyrrolidine-3-carboxamide;N-(benzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(6-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(6-methoxybenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;N-(6-bromobenzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;N-(1H-benzo[d]imidazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(pyridin-2-yl)pyrrolidine-3-carboxamide;N-(5-chloropyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(5-methylpyridin-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-methoxypyridin-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-morpholinopyridin-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(piperidin-1-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;N-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(4-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;N-([2,3′-bipyridin]-6′-yl)-1-cyanopyrrolidine-3-carboxamide;N-([3,3′-bipyridin]-6-yl)-1-cyanopyrrolidine-3-carboxamide;N-([3,4′-bipyridin]-6-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(6-phenylpyridin-3-yl)pyrrolidine-3-carboxamide;1-cyano-(6-phenylpyridazin-3-yl)pyrrolidine-3-carboxamide;1-cyano-N-(2-phenylpyrimidin-5-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-cyclohexylpyridin-2-yl)pyrrolidine-3-carboxamide;N-(1-benzyl-1H-indazol-5-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(1-propyl-1H-benzo[d]imidazol-5-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-methylbenzo[d]thiazol-2-yl)pyrrolidin-3-carboxamide;(S)-1-cyano-N-(7-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)—N-(4-bromobenzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)—N-(7-bromoimidazo[1,2-a]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(pyrazolo[1,5-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-methoxypyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1,8-naphthyridin-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-benzylthiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(isoquinolin-3-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-methyl-5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(4-methoxypiperidin-1-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)—N-(6-(1H-1,2,3-triazol-1-yl)benzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(6-(2H-1,2,3-triazol-2-yl)benzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-(methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-(4-methyl-5-(morpholinomethyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(3,4-difluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(pyridin-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(pyridin-2-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(R)-1-cyano-N-(5-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;(2S,3S)-1-cyano-2-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;(2S,3S)-1-cyano-N-(5-(4-fluorophenyl)thiazol-2-yl)-2-methylpyrrolidine-3-carboxamide;(2S,3S)-1-cyano-2-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(2S,3S)-1-cyano-2-methyl-N-(5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide;(2S,3S)-1-cyano-2-methyl-N-(5-(tetrahydro-2H-pyran-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(2S,3S)—N-(5-(2-chlorophenyl)thiazol-2-yl)-1-cyano-2-methylpyrrolidine-3-carboxamide;1-cyano-3-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-3-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;1-cyano-3-(methoxymethy)-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;1,3-dicyano-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;(3S,4S)-1-cyano-4-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;(3S,4S)-1-cyano-4-methyl-N-(5-methylthiazol-2-yl)pyrrolidine-3-carboxamide;(3S,4S)—N-(5-(2-chlorophenyl)thiazol-2-yl)-1-cyano-4-methylpyrrolidine-3-carboxamide;(3S,4S)-1-cyano-4-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(3S,4S)-1-cyano-4-ethyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;(3S,4S)-1-cyano-4-ethyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;1-cyano-5-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-5-methyl-N-(1-phenyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;1-cyano-5-methyl-N-(5-phenyl-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-morpholinothiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(4-methylpiperazin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;N-(5-(2-(acetamidomethyl)piperidin-1-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(5-(methyl(phenyl)amino)thiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(indolin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(isoindolin-2-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(3,4-dihydroisoquinolin-2(1H)-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-((R)-2-(methoxymethyl)pyrrolidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-((S)-2-(methoxymethyl)pyrrolidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(5-oxo-1,4-diazepan-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(R)-1-cyano-N-(5-morpholinothiazol-2-yl)pyrrolidine-3-carboxamide;(R)-1-cyano-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(3S,4S)-1-cyano-4-methyl-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-5-methyl-N-(5-(piperidin-1-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(pyrrolidin-1-yl)pyrazin-2-yl)pyrrolidine-3-carboxamide;N-(5-(2-aminophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;N-(5-(3-aminophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;N-(5-(4-aminophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(5-(pyridin-3-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(E)-1-cyano-N-(5-(2-cyclopropylvinyl)thiazol-2-yl)pyrrolidine-3-carboxamide;N-(5-(4-acetamidophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;N-(5-(2-acetamidophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;1-cyano-N-(5-(3-(methylsulfonamido)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(3-cyanophenyl)thiazol-2-yl)pyrrolidin-3-carboxamide;(S)-1-cyano-N-(5-(4-cyanophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(3,5-dimethylisoxazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(4-methoxyphenyl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-phenylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(1-methyl-1H-pyrazol-5-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(3,5-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(5-methylisoxazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide1-cyano-N-(6-cyclopropylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(3,6-dimethoxypyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(3,6-dimethoxypyridazin-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(2S,3S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)benzo[d]thiazol-2-yl)-2-methylpyrrolidine-3-carboxamide;1-cyano-N-(5-(p-tolyl)pyridin-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(m-tolyl)pyridin-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(o-tolyl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)-5-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)-7-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(7-methyl-6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(morpholinomethyl)thiazol-2-yl)pyrrolidine-3-carboxamide;1-cyano-N-(5-(pyrrolidin-1-ylmethyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(3S)-1-cyano-N-(5-((2,6-dimethylmorpholino)methyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(2S,3S)-1-cyano-N-(5-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)thiazol-2-yl)-2-methylpyrrolidine-3-carboxamide;(S)—N-(1-benzyl-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-phenethyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-isobutyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(2S,3S)—N-(1-benzyl-1H-imidazol-4-yl)-1-cyano-2-methylpyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(3-fluorophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(2-fluorophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1I-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-(methylcarbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(3-(methylcarbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(2-(methylcarbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-((2-methoxyethyl)carbamoyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(2-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1I-cyclohexyl-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(3S)-1-cyano-N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(2,3-dihydro-1H-inden-2-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-((S)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-((R)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(pyridin-4-ylmethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(2S,3S)-1-cyano-2-methyl-N-(1-((S)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(3S,4S)-1-cyano-4-methyl-N-(1-((S)-1-phenylethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-methylpyridin-2-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1I-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(R)-1-cyano-N-(1-(2-methylpyrimidin-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1I-(4-cyanophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)—N-(1-benzyl-2-methyl-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(3-cyanophenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(pyridin-3-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(pyridin-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(3S)—N-(1-(1-benzoylpiperidin-3-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide;(3S)—N-(1-(1-benzoylpyrrolidin-3-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide;(3S)—N-(1-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide;(3S)-1-cyano-N-(1-(1-methylpiperidin-3-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(3S)-1-cyano-N-(1-(1-methylpyrrolidin-3-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)—N-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-isobutyryl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-benzoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(2-methoxybenzoyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-picolinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(1-methyl-1H-pyrazole-3-carbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyrrolidine-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(1-methyl-2-oxo-1,2-dihydropyridine-3-carbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-nicotinoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(dimethylglycyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidin-3-carboxamide;methyl(S)-2-(1-cyanopyrrolidine-3-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate;2-methoxyethyl(S)-2-(1-cyanopyrrolidine-3-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate;(S)-1-cyano-N-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(isopropylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(phenylsulfonyl)-5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-ethynylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(3-ethynylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(3S)-1-cyano-N-(5-(N-(1-phenylethyl)sulfamoyl)pyridin-2-yl)pyrrolidine-3-carboxamide;(3S)-1-cyano-N-(5-(N-methyl-N-(1-phenylethyl)sulfamoyl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(3S,4S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-4-(trifluoromethyl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(N,N-dimethylsulfamoyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(pyridazin-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-cyano-3-fluorophenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-(1H-indazol-7-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(5-(3-(1H-imidazol-1-yl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-(methylsulfonamido)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-(3-(1H-pyrazol-1-yl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-cyano-3-trifluoromethoxy)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-cyano-3-methoxyphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-sulfamoylphenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-(1H-indazol-6-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(5-(1H-indazol-5-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-6-(2-(1-cyanopyrrolidine-3-carboxamido)thiazol-5-yl)-N-methylpicolinamide;(S)-6-(2-(1-cyanopyrrolidine-3-carboxamido)thiazol-5-yl)-N-ethylpicolinamide;(S)-1-cyano-N-(5-(1-methyl-1H-indazol-5-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(1-(2-methoxyethyl)-1H-indazol-5-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(2-oxoindolin-7-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(3-methyl-1H-indazol-5-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-(1H-indazol-4-yl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(4-fluoro-3-(methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-(3-carbamoylphenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(3-(methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(3-(ethylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(3-(dimethylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-(3-carbamoyl-4-fluorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(5-(3-carbamoyl-4-chlorophenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(5-(4-chloro-3-(methylcarbamoyl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(5-(4-chloro-3-(prop-2-yn-1-ylcarbamoyl)phenyl)thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(isopropylsulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrrolidine-3-carboxamide;(S)—N-(5-benzyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-cyano-3-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(2-cyano-5-(2-methoxyethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-cyano-3-(3-morpholinopropoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(2-cyano-5-(3-morpholinopropoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-cyano-3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(2-cyano-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-cyano-3-(oxetan-3-yloxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(2-cyano-5-(oxetan-3-yloxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-(imidazo[2-a]pyrimidin-5-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-(imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)pyrrolidin-3-carboxamide;(S)-1-cyano-N-(4-(imidazo[1,2-a]pyrazin-6-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-(imidazo[1,2-a]pyrimidin-6-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1,7-naphthyridin-6-yl)pyrrolidine-3-carboxamide;(S)—N-(6-(3-chlorophenyl)pyrimidin-4-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(2′-amino-[4,4′-bipyridin]-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(2′-(methylamino)-[4,4′-bipyridin]-2-yl)pyrrolidine-3-carboxamide;(S)-3-(1-cyanopyrrolidine-3-carboxamido)-N-methylisoquinoline-6-carboxamide;(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide;(S)—N-(4-(1H-indazol-4-yl)pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-ethynylisoquinolin-3-yl)pyrrolidine-3-carboxamide;(2S,3S)-1-cyano-N-(6-ethynylisoquinolin-3-yl)-2-methylpyrrolidine-3-carboxamide;(S)-3-(1 cyanopyrrolidine-3-carboxamido)isoquinoline-&-carboxamide;(2S,3S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-cyano-2-methylpyrrolidine-3-carboxamide;(S)-1-cyano-N-(pyrazolo[1,5-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(pyridin-3-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(pyridin-3-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-methyl-5-(m-tolyl)-1H-pyrazol-3-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(quinolin-3-yl)pyrrolidine-3-carboxamide;(S)—N-(4-(tert-butyl)pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(pyridin-4-yl)pyrimidin-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-phenylpyridazin-3-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(oxazol-5-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(isopropylsulfonyl)-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;3-cyano-N-(5-phenylthiazol-2-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide;2-cyano-N-(5-phenylthiazol-2-yl)-2-azabicyclo[3.1.0]hexane-4-carboxamide;(3S,4S)-1l-cyano-N-(5-phenylthiazol-2-yl)-4-(trifluoromethyl)pyrrolidine-3-carboxamide;(3S,4R)-1-cyano-N-(5-phenylthiazol-2-yl)-4-(pyridin-3-yl)pyrrolidine-3-carboxamide;(3S,4R)-1-cyano-N-(5-phenylthiazol-2-yl)-4-(pyrimidin-5-yl)pyrrolidine-3-carboxamide;1-cyano-3-methoxy-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)thiazolo[4,5-b]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(5-(3,5-dimethylisoxazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(2,6-dimethylphenyl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(1,3-dimethyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(5-(trifluoromethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-(3-(5-methylisoxazol-4-yl)phenyl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)—N-(4-(1H-pyrazol-4-yl)pyridin-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(1-(4-(1H-pyrazol-4-yl)phenyl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(4-(5-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(6-(3,5-dimethylisoxazol-4-yl)thiazolo[4,5-c]pyridin-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(2′-(5-methylisoxazol-4-yl)-[4,4′-bipyridin]-2-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(1,3-dimethyl-1H-indazol-5-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(3-methyl-1H-indazol-6-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)—N-(1-(1H-indazol-5-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide;(S)—N-(1-(1H-indazol-6-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)—N-(1-(1H-indazol-4-yl)-1H-imidazol-4-yl)-1-cyanopyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-cyano-3-cyclopropylphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(quinolin-4-yl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-methyl-N-(4(4-(methylcarbamoyl)phenyl)thiazol-2-yl)pyrrolidine-2-carboxamide;(S)-1-cyano-N-(1-(4-cyano-3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-cyano-3-methylphenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;(S)-1-cyano-N-(1-(4-cyano-3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;and(S)-1-cyano-N-(1-(4-cyano-3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)pyrrolidine-3-carboxamide;a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, together with one or more pharmaceuticallyacceptable excipients.